Hair Growth and Disorders

Ulrike Blume-Peytavi · Antonella Tosti David A. Whiting · Ralph M. Trüeb (Eds.) Hair Growth and Disorders

Ulrike Blume-Peytavi · Antonella Tosti David A. Whiting · Ralph M. Trüeb (Eds.)

Hair Growth and Disorders With 270 Figures and 85 Tables

123

Professor Dr. Ulrike Blume-Peytavi Clinical Research Center for Hair and Skin Science (CRC) Department of Dermatology and Allergy Charité -Universitätsmedizin Berlin Charitéplatz 1 10117 Berlin Germany

Professor Dr. David A. Whiting The Hair and Skin Research and Treatment Center 3600 Gaston Avenue Suite 1058, Wadley Tower Dallas, Texas 75246 USA

Professor Dr. Antonella Tosti Department of Dermatology University of Bologna Via Massarenti, 1 40138 Bologna Italy

Professor Dr. Ralph M. Trüeb Department of Dermatology University Hospital of Zürich Gloriastrasse 31 8091 Zürich Switzerland

ISBN 978-3-540-46908-7               e-ISBN 978-3-540-46911-7 DOI 10.1007/978-3-540-46911-7 Library of Congress Control Number: 2007936859 © 2008 Springer-Verlag Berlin Heidelberg This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: the publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover design: Frido Steinen-Broo, eStudio Calamar, Spain Production & Typesetting: le-tex publishing services oHG, Leipzig, Germany Printed on acid-free paper 987654321 springer.com

Preface

The ideal of lifelong beautiful hair, easy to grow or to eliminate, to pigment or to depigment, to newly create or simply to replace or rearrange, is of interest to anyone interested in hair growth and its disorders, or who has patients with hair problems. During the past 20 years, the interest in hair growth and disorders has dramatically increased. Only 20 years ago the European Hair Research Society was founded, followed by the North American Hair Research Society and the Japanese, Korean and Australasian Research Societies. The regular meetings now held on different disciplines concerning hair reflect the worldwide interest in improving our knowledge and understanding of hair and hair growth. This textbook is testament to that interest, and contains the latest advances and scientific knowledge from the world’s leading experts in hair biology and clinical trichology. In particular it covers pigmentation, genetics, hair diagnostics, pathogenesis and treatment options, hair removal and restoration techniques. Moreover, this textbook contains unique sections on tropical dermatoses of the scalp, ethnic hair and the impact of hair in forensic investigations. The book contains a chapter devoted to natural products for hair care and treatment, as well as a chapter describing hair over the ages and in art. Also, for the first time, this textbook presents a comprehensive chapter on psychocutaneous disorders of the hair and scalp. The textbook has three sections: (i) basic aspects of human hair growth, (ii) hair and scalp disorders, and (iii)

photoepilation, surgery and hair cosmetics. Each chapter provides a synonym box, a “key features” box, a summary for the clinician, and summary tables. Graphics and clinical photographs illustrate the clinical problems and possibilities. Consequently, this textbook has a strong emphasis on visual learning. One of the main goals in editing this textbook has been to reflect the broad spectrum of our understanding of hair growth, the clear concepts behind the pathogenesis, diagnostic procedures, and current treatment options, and to stimulate the reader to delve even deeper into the challenging task of diagnosing and helping their patients with hair problems. We are extremely proud of, and grateful to, the world’s leading experts for their excellent contribution to this textbook. The quality and diversity of topics presented are testament to the devotion of everyone involved in this project. We would like to thank Dr. Kathrin Hillmann, who was key in assembling and preparing this book. In addition, we would like to thank the Berlin team represented by Hannelore Thomas for helping us to realize the dream of a dedicated textbook that reflects the state of the art in the “World of Hair”. Ulrike Blume-Peytavi, Berlin, Germany Antonella Tosti, Bologna, Italy David Whiting, Texas, USA Ralph Trüeb, Zürich, Switzerland

Contents

1

Biology of the Hair Follicle  .. . . . . . .   1 Annika Vogt, Kevin J. McElwee, Ulrike Blume-Peytavi

1.1 1.2 1.3 1.4

Introduction  . . . . . . . . . . . . . . . . . . . . . .   1 History  . . . . . . . . . . . . . . . . . . . . . . . . . . .   1 Hair Follicle Morphogenesis  . . . . . . .   2 Molecular Mediation of Hair Follicle Morphogenesis  .. . . . . . . . . . . . . . . . . . .   3 Anatomy of the Mature Pilosebaceous Unit  . . . . . . . . . . . . . . . .   5 Hair Fiber Properties  . . . . . . . . . . . . . .   6 Hair Follicle Types  .. . . . . . . . . . . . . . . .   9 Lanugo Hair  . . . . . . . . . . . . . . . . . . . . . .   9 Vellus Hair  .. . . . . . . . . . . . . . . . . . . . . . .   9 Intermediate Hair  . . . . . . . . . . . . . . . . .   10 Terminal Hair  .. . . . . . . . . . . . . . . . . . . .   10 Hair Cycling  . . . . . . . . . . . . . . . . . . . . . .   10 Anagen  . . . . . . . . . . . . . . . . . . . . . . . . . . .   11 Catagen  .. . . . . . . . . . . . . . . . . . . . . . . . . .   12 Telogen  . . . . . . . . . . . . . . . . . . . . . . . . . . .   12 Exogen  . . . . . . . . . . . . . . . . . . . . . . . . . . .   12 Kenogen   . . . . . . . . . . . . . . . . . . . . . . . . .   12 Duration of the Hair Cycle   . . . . . . . .   12 Hair Growth and Cycle Regulation Potential of the Dermal Papilla  . . . . .   13 Developmental Pathways, Cytokines, Growth Factors, and Neuroendocrine Factors  . . . . . . .   13 Hair Growth Changes with Age  . . . .   14 Specialized Hair Follicle Compartments  . . . . . . . . . . . . . . . . . . . .   15 Stem Cells  . . . . . . . . . . . . . . . . . . . . . . . .   15 Immunology  . . . . . . . . . . . . . . . . . . . . . .   16 Neuroimmunological and Neuroendocrine Interactions   .   17 Melanocytes  .. . . . . . . . . . . . . . . . . . . . . .   17 Experimental Techniques  . . . . . . . . . .   17 Clinical Relevance  .. . . . . . . . . . . . . . . .   18 Outlook – Future Developments  .. . .   19

1.5 1.6 1.7 1.7.1 1.7.2 1.7.3 1.7.4 1.8 1.8.1 1.8.2 1.8.3 1.8.4 1.8.5 1.8.6 1.8.7 1.8.8 1.9 1.10 1.10.1 1.10.2 1.10.3 1.10.4 1.11 1.12 1.13

Summary for the Clinician   . . . . . . . .   19 2

The Endocrine Control of the Hair Follicle  .. . . . . . . . . . . . . . .   23 Valerie A. Randall

2.1 2.2 2.3

Introduction  . . . . . . . . . . . . . . . . . . . . . . History  . . . . . . . . . . . . . . . . . . . . . . . . . . . Structure and Function of Hair Follicles  .. . . . . . . . . . . . . . . . . . . . . . . . . . Function  .. . . . . . . . . . . . . . . . . . . . . . . . . Changing the Type of Hair by the Hair Follicle Growth Cycle  .. . Endocrine Regulation of Seasonal Changes in Hair Growth  . . . . . . . . . . . Animals  . . . . . . . . . . . . . . . . . . . . . . . . . . Seasonal Variations in Human Hair Growth  . . . . . . . . . . . . . . . . . . . . . . Hormonal Regulation of Human Hair Growth   .. . . . . . . . . . . . . . . . . . . . . Effects of Pregnancy  . . . . . . . . . . . . . . . The Paradoxical Effects of Androgens on Human Hair Follicles  .. . . . . . . . . . . . . . . . . . . . . How Do Androgens Carry Out These Changes?  . . . . . . . . . . . . . . . . . . . Current Model for the Action of Androgens in Hair Follicles  .. . . . . Mechanism of Androgen Action in Hair Follicles  . . . . . . . . . . . . . . . . . . . Support for the Dermal PapillaBased Model of Androgen Action  . . Paracrine Factors in Mesenchymal– Epithelial Interactions in AndrogenRegulated Hair Follicles  .. . . . . . . . . . . Experimental Techniques  . . . . . . . . . . Clinical Relevance and Conclusions, Outlook – Future Developments   . . . Summary for the Clinician   . . . . . . . .

2.3.1 2.3.2 2.4 2.4.1 2.4.2 2.5 2.5.1 2.5.2 2.5.3 2.5.3.1 2.5.3.2 2.5.4 2.5.5 2.5.6 2.6

  24   24   25   25   27   27   27   28   28   28   28   31   31   32   33   33   35   36   36

VIII

Contents

3

Neuroimmunology of the Hair Follicle  .. . . . . . . . . . . . . . .   41 Eva M. J. Peters, Vladimir A. Botchkarev

3.1 3.2 3.3

Introduction  . . . . . . . . . . . . . . . . . . . . . . History  . . . . . . . . . . . . . . . . . . . . . . . . . . . Neuro–Immuno–Epithelial Interactions in Normal and Pathological Hair Growth  .. . . . . Structure and Function of HF Innervation  . . . . . . . . . . . . . . . . . . . . . . . Neuroimmune Regulatory Network Around Normal HFs  .. . . . . . . . . . . . . . Neuroimmune Interactions in Stress-Mediated Hair Growth Inhibition  .. . . . . . . . . . . . . . . . . . . . . . . . Neuroimmunological Interactions in Autoimmune Hair Loss  .. . . . . . . . . Experimental Techniques  . . . . . . . . . . Clinical Relevance  .. . . . . . . . . . . . . . . . Outlook – Future Developments  .. . . Summary for the Clinician  .. . . . . . . .

3.4 3.5 3.6 3.7 3.8 3.9 3.10

  41   42   42

  44   45          

46 47 47 48 48

Biology of Hair Follicle Pigmentation  . . . . . . . . . . . . . . . . . . . .   51 Desmond J. Tobin

4.1 4.2 4.3

Introduction   .. . . . . . . . . . . . . . . . . . . . . History  . . . . . . . . . . . . . . . . . . . . . . . . . . . Structure and Function/ Pathophysiology/Developments   .. . . Origin and Development of the Hair Follicle Pigmentary Unit  . . . . . . . . . . . Comparative Biology of Epidermal and Hair Follicle Melanocytes   . . . . . The Fate of Hair Follicle Melanocytes During the Hair Growth Cycle  .. . . . . . . . . . . . Regulation of Pigmentation in the Hair Follicle  .. . . . . . . . . . . . . . . . Aging of the Follicle Melanocytes and Hair Graying (Canities)  .. . . . . . . Histopathology of Canities   . . . . . . . . Impact of Melanocyte Loss on the Hair Follicle  . . . . . . . . . . . . . . . . Spontaneous Re-Pigmentation of Hair in Canities  .. . . . . . . . . . . . . . . . Clinical Relevance of Hair Pigmentation   .. . . . . . . . . . . . . Disorders Affecting the Hair Follicle Pigmentary Unit  .. . . . . . . . . . . . . . . . . . Alopecia Areata  . . . . . . . . . . . . . . . . . . . Vitiligo  . . . . . . . . . . . . . . . . . . . . . . . . . . .

4.3.2 4.3.3 4.3.4 4.3.5 4.3.5.1 4.3.5.2 4.3.5.3 4.4 4.4.1 4.4.1.1 4.4.1.2

4.4.1.3 4.4.1.4 4.5 4.5.1 4.5.2 4.5.3 4.6 4.6.1

  43

4

4.3.1

 

  52   53   53   53   54   55

Circumscribed Poliosis  . . . . . . . . . . . . Genetic Poliosis  . . . . . . . . . . . . . . . . . . . Experimental Techniques  . . . . . . . . . . Hair Follicle Melanocyte Culture  . . . Whole-Organ Hair follicle Ex Vivo Culture  . . . . . . . . . . . . . . . . . . . Delivery of Agents to the Hair Follicle  .. . . . . . . . . . . . . . . . . . . . . . . . . . . Outlook – Future Developments  .. . . Is Canities Reversible?  . . . . . . . . . . . . . Summary for the Clinician  .. . . . . . . .

       

66 67 67 67

  67        

69 69 69 71

5

Hair Follicle Vascularization and Innervation  .. . . . . . . . . . . . . . . . .   75 Maria Hordinsky, Marna Ericson

5.1 5.2 5.3

Introduction  . . . . . . . . . . . . . . . . . . . . . . History  . . . . . . . . . . . . . . . . . . . . . . . . . . . Structure and Function/ Pathophysiology/Developments  . . . . Substance P  . . . . . . . . . . . . . . . . . . . . . . . Calcitonin Gene Related Peptide  . . . Neurotrophins  . . . . . . . . . . . . . . . . . . . . Nerves, Blood Vessels, and Lymphatic Capillares  . . . . . . . . . . Experimental Techniques  . . . . . . . . . . Alopecia Areata Mouse Model/ Other Animal Models  . . . . . . . . . . . . . Hair Follicle Stem Cells and Regenerative Medicine  .. . . . . . . . Topical Capsaicin  .. . . . . . . . . . . . . . . . . Botulinum Toxin A  .. . . . . . . . . . . . . . . Topical Neurotrophic Agents   . . . . . . Neurometer  .. . . . . . . . . . . . . . . . . . . . . . Clinical Relevance  .. . . . . . . . . . . . . . . . Outlook – Future Developments  .. . . Summary for the Clinician   . . . . . . . .

5.3.1 5.3.2 5.3.3 5.4 5.5 5.5.1 5.5.2 5.5.3 5.5.4 5.5.5 5.5.6 5.6 5.7

  75   76        

76 77 78 78

  78   78   78                

78 79 79 79 80 80 80 81

6

Molecular Genetics of Human Hair Diseases  . . . . . . . . . .   85 Yutaka Shimomura, Abraham Zlotogorski, Angela M. Christiano

  64

6.1 6.2 6.2.1

  64

6.2.1.1

  66   66   66

6.2.1.2 6.2.1.3 6.3

Introduction  . . . . . . . . . . . . . . . . . . . . . . History  . . . . . . . . . . . . . . . . . . . . . . . . . . . Eda-A1/Edar/Edaradd/NF-κB Signaling  .. . . . . . . . . . . . . . . . . . . . . . . . . Structure and Function/ Pathophysiology/Developments  . . . . Experimental Techniques  . . . . . . . . . . Clinical Relevance  .. . . . . . . . . . . . . . . . Hairless   . . . . . . . . . . . . . . . . . . . . . . . . . .

  60   61   62   64

  86   87   87        

87 88 88 88

Contents

6.3.1 6.3.2 6.3.3 6.4 6.4.1 6.4.2 6.4.3 6.5 6.5.1 6.5.2 6.5.3 6.6 6.6.1 6.6.2 6.6.3 6.7 6.7.1 6.7.2 6.7.3 6.8 6.8.1 6.8.2 6.8.3 6.9 6.9.1 6.9.2 6.9.3 6.10 6.10.1 6.10.2 6.10.3 6.11 6.11.1 6.11.2 6.11.3 6.12 6.13

Structure and Function/ Pathophysiology/Developments  . . .   88 Experimental Techniques  . . . . . . . . .   89 Clinical Relevance  .. . . . . . . . . . . . . . .   89 FOXN1 and Hair Keratins  .. . . . . . . .   90 Structure and Function/ Pathophysiology/Developments  . . .   90 Experimental Techniques  . . . . . . . . .   90 Clinical Relevance  .. . . . . . . . . . . . . . .   90 Classical Cadherins  .. . . . . . . . . . . . . .   91 Structure and Function/ Pathophysiology/Developments  . . .   91 Experimental Techniques  . . . . . . . . .   92 Clinical Relevance  .. . . . . . . . . . . . . . .   92 Desmosomal Cadherins  .. . . . . . . . . .   92 Structure and Function/ Pathophysiology/Developments  . . .   92 Experimental Techniques  . . . . . . . . .   94 Clinical Relevance  .. . . . . . . . . . . . . . .   94 Plakophilin 1  .. . . . . . . . . . . . . . . . . . . .   94 Structure and Function/ Pathophysiology/Developments  . . .   94 Experimental Techniques  . . . . . . . . .   94 Clinical Relevance  .. . . . . . . . . . . . . . .   94 Plakoglobin and Desmoplakin   .. . .   94 Structure and Function/ Pathophysiology/Developments  . . .   94 Experimental Techniques  . . . . . . . . .   95 Clinical Relevance  .. . . . . . . . . . . . . . .   95 Corneodesmosin   .. . . . . . . . . . . . . . . .   96 Structure and Function/ Pathophysiology/Developments  . . .   96 Experimental Techniques  . . . . . . . . .   96 Clinical Relevance  .. . . . . . . . . . . . . . .   96 Gap Junction Proteins  . . . . . . . . . . . .   96 Structure and Function/ Pathophysiology/Developments  . . .   96 Experimental Techniques  . . . . . . . . .   97 Clinical Relevance  .. . . . . . . . . . . . . . .   97 Lipase H  .. . . . . . . . . . . . . . . . . . . . . . . .   98 Structure and Function/ Pathophysiology/Developments  . . .   98 Experimental Techniques  . . . . . . . . .   98 Clinical Relevance  .. . . . . . . . . . . . . . .   98 P2RY5  .. . . . . . . . . . . . . . . . . . . . . . . . . .   100 Outlook – Future Developments  .. .   100 Summary for the Clinician   . . . . . . .   100

7

Histology of the Human Hair Follicle  . . . . . . . . . . . . . . . . . . . . .   107 David A. Whiting

7.1 7.2

Introduction  . . . . . . . . . . . . . . . . . . . . .   108 History   .. . . . . . . . . . . . . . . . . . . . . . . . .   108

7.3 7.4 7.5 7.5.1 7.5.2 7.6 7.6.1 7.6.2 7.6.3 7.6.4 7.6.5 7.6.6 7.6.6.1 7.6.6.2 7.6.7 7.7 7.8 7.9

Structure and Function   .. . . . . . . . . .   Normal Hair Growth Cycle  .. . . . . . .   Biopsies of Human Scalp  .. . . . . . . . .   Vertical Section  . . . . . . . . . . . . . . . . . .   Horizontal Section  . . . . . . . . . . . . . . .   Follicular Anatomy  .. . . . . . . . . . . . . .   Terminal Anagen Hair   . . . . . . . . . . .   Hair Bulb  . . . . . . . . . . . . . . . . . . . . . . . .   Isthmus  .. . . . . . . . . . . . . . . . . . . . . . . . .   Follicular Units   . . . . . . . . . . . . . . . . . .   Vellus Hairs   . . . . . . . . . . . . . . . . . . . . .   Catagen and Telogen Phase  . . . . . . .   Terminal Catagen Hair  .. . . . . . . . . . .   Terminal Telogen Hair  .. . . . . . . . . . .   Follicular Counts and Image Analysis  . . . . . . . . . . . . . . . . . . . . . . . . .   Experimental Techniques  . . . . . . . . .   Clinical Relevance  .. . . . . . . . . . . . . . .   Outlook – Future Developments  .. .   Summary for the Clinician  .. . . . . . .  

IX

108 108 109 109 109 109 109 109 114 114 114 114 114 119 121 121 122 122 122

8

Hair Growth Assessment Techniques  .. . . . . . . . . . . . . . . . . . . . .   125 Ulrike Blume-Peytavi, Kathrin Hillmann, Marcella Guarrera

8.1 8.2 8.3 8.3.1 8.3.2 8.3.2.1 8.4 8.4.1 8.4.1.1 8.4.1.2 8.4.2 8.4.2.1 8.4.2.2 8.4.3 8.4.3.1 8.4.3.2 8.4.4 8.4.4.1 8.4.4.2 8.4.5 8.4.5.1 8.4.5.2 8.4.6 8.4.6.1 8.4.6.2 8.4.7 8.4.7.1

Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Hair Measurement Scores  .. . . . . . . .   Scalp Hair Distribution  . . . . . . . . . . .   Body Hair Distribution  . . . . . . . . . . .   Ferriman and Gallwey Score  . . . . . .   Hair Growth  . . . . . . . . . . . . . . . . . . . . .   Hair Pull Test  . . . . . . . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   Technology  . . . . . . . . . . . . . . . . . . . . . .   Wash Test (Modified)  .. . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   Technology  . . . . . . . . . . . . . . . . . . . . . .   Hair Weighing  . . . . . . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   Technology  . . . . . . . . . . . . . . . . . . . . . .   Global Photographs  . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   Technology  . . . . . . . . . . . . . . . . . . . . . .   Unit Area Trichogram  . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   Technology  . . . . . . . . . . . . . . . . . . . . . .   Trichogram  . . . . . . . . . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   Technology  . . . . . . . . . . . . . . . . . . . . . .   Phototrichogram (PTG)  . . . . . . . . . .   Conventional and ContrastEnhanced (CE) PTG  .. . . . . . . . . . . . .  

126 126 127 127 127 129 130 130 130 130 132 132 132 132 132 132 133 133 134 134 134 134 135 135 135 136 137

X

Contents

8.4.7.2 8.4.8 8.4.8.1 8.4.8.2 8.5 8.5.1 8.5.1.1 8.5.1.2 8.5.1.3 8.5.2 8.5.2.1 8.5.2.2 8.5.2.3 8.5.3 8.5.3.1 8.5.3.2 8.5.4 8.5.4.1 8.5.4.2 8.5.5 8.5.5.1 8.5.5.2 8.5.5.3 8.5.5.4 8.5.5.5 8.5.6 8.5.6.1 8.5.6.2 8.5.7 8.5.7.1 8.5.7.2 8.5.8 8.5.8.1 8.5.8.2 8.5.8.3 8.5.8.4

Automated PTG: TrichoScan  .. . . . .   Videodermoscopy  . . . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   Technology  . . . . . . . . . . . . . . . . . . . . . .   Structural and Functional Investigation  . . . . . . . . . . . . . . . . . . . . .   Mechanical Test of Hair Quality (Elasticity, Strength, Fragility)  .. . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   Mechanical Properties  . . . . . . . . . . . .   Technique  .. . . . . . . . . . . . . . . . . . . . . . .   Optical Light and Polarizing Microscopy  .. . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Technology  . . . . . . . . . . . . . . . . . . . . . .   Confocal Laser Scanning Microscopy (CLSM)  .. . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   Technology  . . . . . . . . . . . . . . . . . . . . . .   Electron Microscopy  .. . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   Technology  . . . . . . . . . . . . . . . . . . . . . .   Atomic Force Microscopy (AFM)  .  Introduction  . . . . . . . . . . . . . . . . . . . . .   Indication  .. . . . . . . . . . . . . . . . . . . . . . .   Technical Procedure  .. . . . . . . . . . . . .   Complications  .. . . . . . . . . . . . . . . . . . .   Combination Possibilities and Practical Advice  .. . . . . . . . . . . . .   Optical Coherence Tomography  .. .   Introduction  . . . . . . . . . . . . . . . . . . . . .   Technology  . . . . . . . . . . . . . . . . . . . . . .   Hair Analysis Methods   .. . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   Technology  . . . . . . . . . . . . . . . . . . . . . .   Scalp Biopsy  . . . . . . . . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   Technology  . . . . . . . . . . . . . . . . . . . . . .   Horizontal sectioning  .. . . . . . . . . . . .   Vertical Sectioning  . . . . . . . . . . . . . . .   Summary for the Clinician  .. . . . . . .  

 

138 140 140 141

9.4.1 9.5 9.5.1 9.6

142

9.7 9.7.1 9.7.2 9.8 9.8.1 9.8.2 9.8.2.1 9.8.2.2 9.8.2.3 9.8.3 9.8.4

142 142 142 142 142 142 142 142 143 143 144 144 144 146 146 146 146 146 146 146 148 148 148 148 148 149 151 151 151 152 153 154

9

Male Androgenetic Alopecia  . . . .   159 Andrew Messenger

9.1 9.2 9.3 9.3.1 9.3.2 9.3.3 9.4

Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Aetiology  . . . . . . . . . . . . . . . . . . . . . . . .   Androgens  .. . . . . . . . . . . . . . . . . . . . . .   Genetics  . . . . . . . . . . . . . . . . . . . . . . . . .   Age   . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .  

160 160 161 161 161 162 163

Prevalence  . . . . . . . . . . . . . . . . . . . . . . .   Pathophysiology of Male Balding  .   Histopathology  .. . . . . . . . . . . . . . . . . .   Psychosocial Effects of Male Balding  . . . . . . . . . . . . . . . . . .   Associated Pathologies  .. . . . . . . . . . .   Coronary Heart Disease  . . . . . . . . . .   Prostate Cancer  . . . . . . . . . . . . . . . . . .   Management  . . . . . . . . . . . . . . . . . . . . .   Counselling  .. . . . . . . . . . . . . . . . . . . . .   Medical Treatments  .. . . . . . . . . . . . . .   Minoxidil  .. . . . . . . . . . . . . . . . . . . . . . .   Finasteride  .. . . . . . . . . . . . . . . . . . . . . .   Minoxidil versus Finasteride  . . . . . .   Surgery  . . . . . . . . . . . . . . . . . . . . . . . . . .   Cosmetics  .. . . . . . . . . . . . . . . . . . . . . . .   Summary for the Clinician  .. . . . . . .  

164 164 165 165 165 165 165 166 166 166 166 167 167 167 168 168

10

Female Pattern Hair Loss  . . . . . . . .   171 Elise A. Olsen

10.1 10.2 10.3 10.4 10.4.1 10.4.2 10.4.3 10.5 10.6 10.7 10.8 10.9 10.9.1 10.9.2 10.9.3 10.9.4 10.9.5 10.9.6 10.9.7 10.9.8 10.9.9 10.9.10 10.10

Introduction   .. . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology   .. . . . . . . . . . . . . . . . . . .   Pathophysiology   . . . . . . . . . . . . . . . . .   Androgens   . . . . . . . . . . . . . . . . . . . . . .   Estrogens   .. . . . . . . . . . . . . . . . . . . . . . .   Genetics  . . . . . . . . . . . . . . . . . . . . . . . . .   Clinical Features   .. . . . . . . . . . . . . . . .   Histopathology  .. . . . . . . . . . . . . . . . . .   Differential Diagnosis   .. . . . . . . . . . .   Evaluation   .. . . . . . . . . . . . . . . . . . . . . .   Medical Treatment   .. . . . . . . . . . . . . .   Topical Minoxidil   .. . . . . . . . . . . . . . .   Antiandrogens   .. . . . . . . . . . . . . . . . . .   Spironolactone   .. . . . . . . . . . . . . . . . . .   Flutamide   . . . . . . . . . . . . . . . . . . . . . . .   Cyproterone Acetate   . . . . . . . . . . . . .   Other Antiandrogens   . . . . . . . . . . . .   5α-Reductase Inhibitors   .. . . . . . . . .   Estrogens   .. . . . . . . . . . . . . . . . . . . . . . .   Estrogen Receptor Antagonist   . . . .   Melatonin  .. . . . . . . . . . . . . . . . . . . . . . .   Surgical Treatment  . . . . . . . . . . . . . . .   Summary for the Clinician  .. . . . . . .  

11

Primary Cicatricial Alopecia  . . . . .   187 Elizabeth Katrina Ross, Jerry Shapiro

11.1

Approach to the Patient with Cicatricial Alopecia  .. . . . . . . . . . . . . .   189 Classification   . . . . . . . . . . . . . . . . . . . .   189

11.2

172 172 173 173 173 175 176 176 177 177 178 179 179 180 180 181 181 182 182 182 182 182 183 183

Contents

11.3 11.3.1 11.3.1.1 11.3.2 11.3.2.1 11.3.2.2 11.3.2.3 11.3.2.4 11.3.2.5 11.3.2.6 11.3.2.7 11.3.3 11.3.3.1 11.3.3.2 11.3.3.3 11.3.3.4 11.3.3.5 11.3.3.6 11.3.3.7 11.3.4 11.3.5 11.3.5.1 11.3.5.2 11.3.5.3 11.3.5.4 11.3.5.5 11.3.5.6 11.3.5.7 11.3.6 11.3.6.1 11.3.6.2 11.3.6.3 11.3.6.4 11.3.6.5 11.3.6.6 11.3.6.7 11.3.7 11.3.7.1 11.3.7.2 11.3.7.3 11.3.7.4 11.3.7.5 11.3.7.6 11.3.7.7 11.3.8 11.3.8.1 11.3.8.2 11.3.8.3 11.3.8.4 11.3.8.5

Lymphocytic Disorders  . . . . . . . . . . .   Lichen Planopilaris  . . . . . . . . . . . . . . .   Classic Lichen Planopilaris  .. . . . . . .   Frontal Fibrosing Alopecia  .. . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Piccardi–Lassueur–Graham Little Syndrome  . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Fibrosing Alopecia in a Pattern Distribution  . . . . . . . . . .   Pseudopelade of Brocq  .. . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Central Centrifugal Cicatricial Alopecia  . . . . . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Alopecia Mucinosa  . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Keratosis Follicularis Spinulosa Decalvans (KFSD)  .. . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .  

189 189 190 193 193 193 193 193 194 194 194 195 195 195 195 195 195 195 195 195 196 196 196 197 197 198 198 198 198 198 199 199 199 199 199 200 200 200 200 200 201 201 201 202 202 202 203 203 203 204

11.3.8.6 11.3.8.7 11.3.9 11.3.9.1 11.3.9.2 11.3.9.3 11.3.9.4 11.3.9.5 11.3.9.6 11.3.9.7 11.4 11.4.1 11.4.1.1 11.4.1.2 11.4.1.3 11.4.1.4 11.4.1.5 11.4.1.6 11.4.1.7 11.4.2 11.4.2.1 11.4.2.2 11.4.2.3 11.4.2.4 11.4.2.5 11.4.2.6 11.4.2.7 11.5 11.5.1 11.5.1.1 11.5.1.2 11.5.1.3 11.5.1.4 11.5.1.5 11.5.1.6 11.5.1.7 11.5.2 11.5.2.1 11.5.2.2 11.5.2.3 11.5.2.4 11.5.2.5 11.5.2.6 11.5.2.7 11.5.3 11.5.3.1 11.5.3.2 11.5.3.3 11.5.3.4 11.5.3.5 11.5.3.6 11.5.3.7

Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Discoid Lupus Erythematosus  .. . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features   .. . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Neutrophilic Disorders  . . . . . . . . . . .   Folliculitis Decalvans  . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  .. . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . .   Perifolliculitis Abscedens et Suffodiens  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Mixed Cicatricial Alopecia  .. . . . . . .   Acne Keloidalis  .. . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Acne Necrotica   . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Erosive Pustular Dermatosis  . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .  

XI

204 204 205 205 205 205 205 206 207 207 208 208 208 208 208 208 208 209 209 211 211 211 211 212 213 213 213 214 214 214 214 214 215 215 215 215 216 217 217 217 217 217 217 217 218 218 218 218 218 219 219 219

XII

Contents

11.6 11.7

Surgical Correction of Burnt-Out Cicatricial Alopecia  .. . . . . . . . . . . . . .   219 General Measures for Management of Cicatricial Alopecia  . . . . . . . . . . . .   219 Summary for the Clinician  .. . . . . . .   220

12

Secondary Cicatricial and other Permanent Alopecias  .   227 Andreas M. Finner, Jerry Shapiro

12.1 12.2

Introduction  . . . . . . . . . . . . . . . . . . . . .   Genodermatoses and Developmental Defects with Alopecia   .. . . . . . . . . . .   Ectodermal Dysplasias  .. . . . . . . . . . .   Aplasia Cutis Congenita  . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Incontinentia Pigmenti   .. . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Ichthyosis  .. . . . . . . . . . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   X-Chromosomal Chondrodysplasia Punctata  . . . . . . . . . . . . . . . . . . . . . . . . .   Hereditary Epidermolysis Bullosa (EB)  . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Porokeratosis of Mibelli  .. . . . . . . . . .   Meningoceles  . . . . . . . . . . . . . . . . . . . .   Generalized Hamartoma  .. . . . . . . . .   True Epidermal and Organoid Epidermal Nevi   . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .  

12.2.1 12.2.2 12.2.2.1 12.2.2.2 12.2.2.3 12.2.2.4 12.2.2.5 12.2.2.6 12.2.2.7 12.2.2.8 12.2.3 12.2.3.1 12.2.3.2 12.2.3.3 12.2.3.4 12.2.3.5 12.2.3.6 12.2.4 12.2.4.1 12.2.4.2 12.2.4.3 12.2.4.4 12.2.4.5 12.2.5 12.2.6 12.2.6.1 12.2.6.2 12.2.6.3 12.2.6.4 12.2.6.5 12.2.6.6 12.2.6.7 12.2.7 12.2.8 12.2.9 12.2.10 12.2.10.1

228 230 230 230 230 231 231 231 231 231 231 232 232 232 232 232 232 232 232 233 233 233 233 233 233 234 234 235 235 235 235 235 235 235 235 236 236 236 236

 

12.2.10.2 12.2.10.3 12.2.10.4 12.2.10.5 12.2.10.6 12.2.10.7 12.2.11 12.2.12 12.2.13 12.3 12.3.1 12.3.1.1 12.3.1.2 12.3.1.3 12.3.1.4 12.3.1.5 12.3.1.6 12.3.2 12.3.2.1 12.3.2.2 12.3.3 12.3.4 12.3.4.1 12.3.4.2 12.3.4.3 12.3.5 12.3.6 12.3.7 12.3.7.1 12.3.7.2 12.3.7.3 12.3.7.4 12.3.7.5 12.4 12.4.1 12.4.1.1 12.4.1.2 12.4.1.3 12.4.1.4 12.4.2 12.4.2.1 12.4.3 12.4.3.1 12.5 12.5.1 12.5.2 12.5.3 12.5.4 12.5.5

Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Vascular Malformations  .. . . . . . . . . .   Dyskeratosis Follicularis  . . . . . . . . . .   Fibrodysplasias  .. . . . . . . . . . . . . . . . . .   Physical and Chemical Injury  . . . . .   Mechanical Trauma  .. . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Prophylaxis  . . . . . . . . . . . . . . . . . . . . . .   Burns  .. . . . . . . . . . . . . . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Freezing  . . . . . . . . . . . . . . . . . . . . . . . . .   Chemical Injury  .. . . . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Scratching  . . . . . . . . . . . . . . . . . . . . . . .   Insect Bites  .. . . . . . . . . . . . . . . . . . . . . .   Radiation   .. . . . . . . . . . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Infections  .. . . . . . . . . . . . . . . . . . . . . . .   Bacterial  . . . . . . . . . . . . . . . . . . . . . . . . .   Carbuncle  .. . . . . . . . . . . . . . . . . . . . . . .   Leprosy  .. . . . . . . . . . . . . . . . . . . . . . . . .   Tertiary Syphilis  .. . . . . . . . . . . . . . . . .   Cutaneous Tuberculosis  .. . . . . . . . . .   Viral  .. . . . . . . . . . . . . . . . . . . . . . . . . . . .   Zoster and Varicella  . . . . . . . . . . . . . .   Fungal  .. . . . . . . . . . . . . . . . . . . . . . . . . .   Tinea Capitis  .. . . . . . . . . . . . . . . . . . . .   Inflammatory Dermatoses  . . . . . . . .   Psoriasis   .. . . . . . . . . . . . . . . . . . . . . . . .   Pityriasis Amiantacea  .. . . . . . . . . . . .   Giant Cell Arteritis  . . . . . . . . . . . . . . .   Pyoderma Gangrenosum  .. . . . . . . . .   Graft-Versus-Host Disease (GVHD)  .. . . . . . . . . . . . . . . . . . . . . . . .   12.5.6 Morphea and Facial Hemiatrophy  .   12.5.6.1 Introduction  . . . . . . . . . . . . . . . . . . . . .   12.5.6.2 Epidemiology  . . . . . . . . . . . . . . . . . . . .   12.5.6.3 Pathogenesis  . . . . . . . . . . . . . . . . . . . . .  

236 236 236 237 237 237 237 237 238 238 238 238 238 238 238 238 239 239 239 239 239 240 240 240 240 240 240 240 240 241 241 242 242 242 242 242 242 242 242 242 242 243 243 246 246 246 246 247 247 248 248 248 249

Contents

12.5.6.4 12.5.6.5 12.5.6.6 12.5.6.7 12.5.7 12.5.8 12.5.9 12.5.9.1 12.5.9.2 12.5.9.3 12.5.9.4 12.5.9.5 12.5.9.6 12.5.10 12.5.11 12.5.11.1 12.5.11.2 12.5.11.3 12.5.11.4 12.5.11.5 12.5.11.6 12.5.11.7 12.5.11.8 12.6 12.6.1 12.6.1.1 12.6.1.2 12.6.1.3 12.6.1.4 12.7

Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Lichen Sclerosus and Atrophicus  .  Cicatricial Pemphigoid  .. . . . . . . . . . .   Porphyria Cutanea Tarda  .. . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Epidermolysis Bullosa Acquisita   . .   Sarcoidosis  .. . . . . . . . . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Drugs  .. . . . . . . . . . . . . . . . . . . . . . . . . . .   Drug-induced Permanent Hair Loss  . . . . . . . . . . . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Neoplasms  .. . . . . . . . . . . . . . . . . . . . . .   Summary for the Clinician  .. . . . . . .  

249 250 250 250 250 250 251 251 251 251 251 251 251 251 251 252 252 252 252 252 252 252 252 253 253 253 253 253 253 253 253

13

Diffuse Hair Loss  . . . . . . . . . . . . . . . .   259 Ralph M. Trüeb

13.1 13.2 13.3 13.3.1 13.3.2 13.3.2.1 13.3.2.2

Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Hair Follicle Cycling  .. . . . . . . . . . . . .   Pathologic Dynamics of Hair Loss  .   Dystrophic Anagen Effluvium  .. . . .   Functional Types of Telogen Effluvium  . . . . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Anagen Effluvium  . . . . . . . . . . . . . . . .   Dystrophic Anagen Effluvium  .. . . .   Loose Anagen Hair  . . . . . . . . . . . . . . .   Telogen Effluvium  . . . . . . . . . . . . . . . .   Acute Telogen Effluvium  .. . . . . . . . .   Chronic Telogen Effluvium  .. . . . . . .   Quantitating Hair Loss  .. . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .  

13.4 13.4.1 13.4.1.1 13.4.1.2 13.4.2 13.4.2.1 13.4.2.2 13.4.3 13.5

260 260 260 260 261 261 261 262 262 262 264 264 264 264 265 268

13.5.1 13.5.1.1 13.5.2 13.5.2.1 13.5.2.2 13.5.2.3

Androgenetic Alopecia  . . . . . . . . . . .   Female Pattern Hair Loss  . . . . . . . . .   Psychogenic Pseudoeffluvium  . . . . .   Alopeciaphobia  .. . . . . . . . . . . . . . . . . .   Telogen Mania  . . . . . . . . . . . . . . . . . . .   Delusion of Alopecia/Body Dysmorphic Disorder  .. . . . . . . . . . . .   13.5.3 Alopecia Areata  . . . . . . . . . . . . . . . . . .   13.5.3.1 Diffuse Alopecia Areata  .. . . . . . . . . .   13.5.3.2 Chronic Diffuse Alopecia Areata/ Diffuse Alopecia with Stem Cell Folliculitis  . . . . . . . . . . . . . . . . . . . . . . .   13.6 Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Summary for the Clinician  .. . . . . . .  

XIII

268 268 268 268 268 268 268 269 269 269 270

14

Hair Loss in Children  . . . . . . . . . . . .   273 Natalie Garcia Bartels, Ulrike Blume-Peytavi

14.1

Hair Shaft Defects Simulating Hair Loss  . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   Trichorrhexis Nodosa Congenita  .  Introduction   .. . . . . . . . . . . . . . . . . . . .   History   .. . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis   .. . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology   . . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis   .. . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Monilethrix  .. . . . . . . . . . . . . . . . . . . . .   Introduction   .. . . . . . . . . . . . . . . . . . . .   History   .. . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis   .. . . . . . . . . . . . . . . . . . . .   Clinical Features   .. . . . . . . . . . . . . . . .   Pathology   . . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment   . . . . . . . . . . . . . . . . . . . . . . .   Pseudomonilethrix  . . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History   .. . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology   .. . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features   .. . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment   . . . . . . . . . . . . . . . . . . . . . . .   Pili Torti  .. . . . . . . . . . . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .  

14.1.1 14.1.1.1 14.1.1.2 14.1.1.3 14.1.1.4 14.1.1.5 14.1.1.6 14.1.1.7 14.1.1.8 14.1.2 14.1.2.1 14.1.2.2 14.1.2.3 14.1.2.4 14.1.2.5 14.1.2.6 14.1.2.7 14.1.2.8 14.1.3 14.1.3.1 14.1.3.2 14.1.3.3 14.1.3.4 14.1.3.5 14.1.3.6 14.1.3.7 14.1.3.8 14.1.4 14.1.4.1 14.1.4.2 14.1.4.3 14.1.4.4

276 276 277 277 278 278 278 278 278 278 278 278 279 279 279 279 280 280 280 280 280 280 281 281 281 281 281 281 281 281 281 281 282

XIV

Contents

14.1.4.5 14.1.4.6 14.1.4.7 14.1.4.8 14.1.5 14.1.5.1 14.1.5.2 14.1.5.3 14.1.5.4 14.1.5.5 14.1.5.6 14.1.5.7 14.1.5.8 14.1.6 14.1.6.1 14.1.6.2 14.1.6.3 14.1.6.4 14.1.6.5 14.1.6.6 14.1.6.7 14.1.6.8 14.1.7 14.1.7.1 14.1.7.2 14.1.7.3 14.1.7.4 14.1.7.5 14.1.7.6 14.1.7.7 14.1.7.8 14.1.8 14.1.8.1 14.1.8.2 14.1.8.3 14.1.8.4 14.1.8.5 14.1.8.6 14.1.8.7 14.1.8.8 14.1.9 14.1.9.1 14.1.9.2 14.1.9.3 14.1.9.4 14.1.9.5 14.1.9.6 14.1.9.7 14.1.9.8 14.2 14.2.1 14.2.1.1 14.2.1.2 14.2.1.3

Clinical Features   .. . . . . . . . . . . . . . . .   Pathology   . . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Menkes Disease  . . . . . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History   .. . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology   .. . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features   .. . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment   . . . . . . . . . . . . . . . . . . . . . . .   Netherton Syndrome  . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology   .. . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features   .. . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis   .. . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Trichothiodystrophy  .. . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History   .. . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology   .. . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features   .. . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment   . . . . . . . . . . . . . . . . . . . . . . .   Ectodermal Dysplasia  .. . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History   .. . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology   .. . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features   .. . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment   . . . . . . . . . . . . . . . . . . . . . . .   Acquired Hair Shaft Defects with Fractures: Weathering  .. . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features   .. . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Localized Hair Loss   . . . . . . . . . . . . . .   Non-Scarring Alopecia  . . . . . . . . . . .   Alopecia Areata  . . . . . . . . . . . . . . . . . .   Tinea Capitis  .. . . . . . . . . . . . . . . . . . . .   Trichotillomania  . . . . . . . . . . . . . . . . .  

282 282 282 283 283 283 283 283 283 284 284 284 284 284 284 284 284 285 285 285 286 286 286 286 286 286 286 287 287 287 287 287 287 288 288 288 288 289 289 289 290 290 290 290 290 290 290 291 291 291 291 291 292 293

 

14.2.1.4 14.2.1.5 14.2.2 14.2.2.1 14.3 14.3.1 14.3.1.1 14.3.1.2 14.3.1.3 14.3.1.4 14.3.1.5 14.3.1.6 14.3.2 14.3.2.1 14.3.2.2

Traction Alopecia  . . . . . . . . . . . . . . . .   Triangular Alopecia  . . . . . . . . . . . . . .   Scarring Alopecia  . . . . . . . . . . . . . . . .   Congenital Aplasia Cutis  .. . . . . . . . .   Diffuse Hair Loss   . . . . . . . . . . . . . . . .   Non-Scarring Alopecia  . . . . . . . . . . .   Telogen Effluvium  . . . . . . . . . . . . . . . .   Alopecia Areata Diffusa, Totalis or Universalis  . . . . . . . . . . . . .   Loose Anagen Hair  . . . . . . . . . . . . . . .   Hypotrichosis Simplex  .. . . . . . . . . . .   Congenital Hypotrichia Marie Unna  .. . . . . . . . . . . . . . . . . . . . .   Atrichia with Papular Lesions  . . . . .   Scarring Alopecia  . . . . . . . . . . . . . . . .   Keratosis Follicularis Spinulosa Decalvans  .. . . . . . . . . . . . . . . . . . . . . . .   Pseudopelade of Brocq  .. . . . . . . . . . .   Summary for the Clinician  .. . . . . . .  

294 295 296 296 297 297 298 299 299 301 301 302 303 303 304 305

15

Alopecia Areata  . . . . . . . . . . . . . . . . .   311 Pia Freyschmidt-Paul, Rolf Hoffmann, Kevin J. McElwee

15.1 15.2 15.3 15.4 15.4.1 15.4.1.1 15.4.1.2 15.4.2 15.4.2.1

Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Genetics  . . . . . . . . . . . . . . . . . . . . . . . . .   Rodent Models  .. . . . . . . . . . . . . . . . . .   Humans  . . . . . . . . . . . . . . . . . . . . . . . . .   Immunology  . . . . . . . . . . . . . . . . . . . . .   Susceptibility Modifying and Causal Factors in AA  . . . . . . . . .   Disease Activation Mechanisms in AA  .. . . . . . . . . . . . . . . . . . . . . . . . . . .   Modes of Immune System Action on Hair Follicles Leading to Hair Loss  .. . . . . . . . . . . . . . . . . . . . .   Modes of Hair Follicle Response to Immune Activity Leading to Hair Loss  . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment   . . . . . . . . . . . . . . . . . . . . . . .   Immunosuppressive Treatments  .. .   Corticosteroids  .. . . . . . . . . . . . . . . . . .   Topical Corticosteroids   .. . . . . . . . . .   Intralesional Corticosteroids   .. . . . .   Systemic Corticosteroids   . . . . . . . . .   Psoralen UV A Therapy   . . . . . . . . . .   The 308-nm Excimer Laser   . . . . . . .   Immunomodulatory Treatments  .. .  

15.4.2.2 15.4.2.3 15.4.2.4 15.5 15.6 15.7 15.8 15.8.1 15.8.1.1 15.8.1.2 15.8.1.3 15.8.1.4 15.8.2 15.8.2.1 15.8.3

312 312 312 312 312 313 313 315 315 316 317 318 320 322 322 322 323 323 323 324 324 325 325 325

Contents

15.8.3.1 Diphenylcyclopropenone and Squaric Acid Dibutylester   . . . .   15.8.3.2 Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   15.8.3.3 Side-Effects  . . . . . . . . . . . . . . . . . . . . . .   15.8.3.4 Studies  .. . . . . . . . . . . . . . . . . . . . . . . . . .   15.8.3.5 Mode of Action  . . . . . . . . . . . . . . . . . .   15.8.4 Other Treatments  .. . . . . . . . . . . . . . . .   15.8.4.1 Irritant Contact Dermatitis – Anthralin   .. . . . . . . . . .   15.8.4.2 Minoxidil   . . . . . . . . . . . . . . . . . . . . . . .   15.8.4.3 Biologics  .. . . . . . . . . . . . . . . . . . . . . . . .   Summary for the Clinician   . . . . . . .  

325 325 325 326 326 328 328 328 328 328

16

Hypertrichosis  . . . . . . . . . . . . . . . . . .   333 Francisco M. Camacho-Martínez

16.1 16.2 16.3 16.3.1

Introduction  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Generalized Hypertrichosis  . . . . . . .   Congenital Hypertrichosis Lanuginosa  . . . . . . . . . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Acquired Hypertrichosis Lanuginosa  . . . . . . . . . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Universal Hypertrichosis  .. . . . . . . . .   Introduction and History  . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Prepubertal Hypertrichosis  .. . . . . . .   Localized Hypertrichosis   . . . . . . . . .   Congenital Localized Hypertrichosis  . . . . . . . . . . . . . . . . . . .   Melanocytic Nevus  . . . . . . . . . . . . . . .   Becker’s Nevus  . . . . . . . . . . . . . . . . . . .   Nevoid Hypertrichosis  .. . . . . . . . . . .   Spinal Dysraphism  . . . . . . . . . . . . . . .   Acquired Localized Hypertrichosis  .  Symptomatic Hypertrichosis  . . . . . .   Hypertrichosis in Congenital and Hereditary Diseases  . . . . . . . . . .   Lipoatrophy (Lawrence-Seip Syndrome)  .. . . . . . .   Cornelia de Lange Syndrome  .. . . . .   Craniofacial Dysostosis  .. . . . . . . . . .   Winchester Syndrome  . . . . . . . . . . . .   Rubinstein-Taybi Syndrome  .. . . . . .   Mucopolysaccharidoses (MPS)  .. . .   Dystrophic Epidermolysis Bullosa  .   Porphyrias  . . . . . . . . . . . . . . . . . . . . . . .  

16.3.1.1 16.3.1.2 16.3.1.3 16.3.2 16.3.2.1 16.3.2.2 16.3.2.3 16.3.2.4 16.3.3 16.3.3.1 16.3.3.2 16.3.4 16.4 16.4.1 16.4.1.1 16.4.1.2 16.4.1.3 16.4.1.4 16.4.2 16.5 16.5.1 16.5.1.1 16.5.1.2 16.5.1.3 16.5.1.4 16.5.1.5 16.5.1.6 16.5.1.7 16.5.1.8

334 334 334 334 334 334 335 335 335 335 335 336 336 336 336 336 336 336 336 338 339 342 343 344 344 344 344 345 345 345 345 345 346

16.5.1.9 Osteochondrodysplasia  . . . . . . . . . . .   16.5.1.10 Gingival Fibromatosis (OMIN: 135400)  . . . . . . . . . . . . . . . . .   16.5.1.11 Globoid Leukodystrophy (Krabbe Disease)  . . . . . . . . . . . . . . . . .   16.5.1.12 Piebaldism  .. . . . . . . . . . . . . . . . . . . . . .   16.5.1.13 Waardenburg’s Syndrome  . . . . . . . . .   16.5.1.14 Hammersehlag-Telfer Syndrome  . .   16.5.1.15 Districhiasis-Lymphedema Syndrome  .. . . . . . . . . . . . . . . . . . . . . . .   16.5.1.16 Oliver-McFarlane’s Syndrome (Trichomegaly Syndrome)  . . . . . . . .   16.5.1.17 Ito’s Type Incontinentia Pigmenti Achromians  .. . . . . . . . . . . . . . . . . . . . .   16.5.2 Acquired Hypertrichosis  .. . . . . . . . .   16.5.2.1 Symptomatic Porphyria Cutanea Tarda  . . . . . . . . . . . . . . . . . . . . . . . . . . . .   16.5.2.2 Cerebral Alterations  . . . . . . . . . . . . . .   16.5.2.3 Syringomyelia and Other Neurological Lesions  . . . . . . . . . . . . .   16.5.2.4 Anorexia Nervosa  . . . . . . . . . . . . . . . .   16.5.2.5 Malnutrition  . . . . . . . . . . . . . . . . . . . . .   16.5.2.6 Acrodynia  . . . . . . . . . . . . . . . . . . . . . . .   16.5.2.7 Dermatomyositis  . . . . . . . . . . . . . . . . .   16.5.2.8 Hypothyroidism  .. . . . . . . . . . . . . . . . .   16.5.2.9 Pretibial Myxedema  . . . . . . . . . . . . . .   16.5.2.10 Fetal Alcohol Syndrome  . . . . . . . . . .   16.5.2.11 POEMS Syndrome  .. . . . . . . . . . . . . . .   16.5.2.12 Acquired Immunodeficiency Syndrome (AIDS)  . . . . . . . . . . . . . . . .   16.5.3 Iatrogenic Hypertrichosis  . . . . . . . . .   16.5.3.1 Antibiotics  . . . . . . . . . . . . . . . . . . . . . .   16.5.3.2 Anti-inflammatory Drugs  .. . . . . . . .   16.5.3.3 Vasodilators  .. . . . . . . . . . . . . . . . . . . . .   16.5.3.4 Diuretics  .. . . . . . . . . . . . . . . . . . . . . . . .   16.5.3.5 Anticonvulsants  .. . . . . . . . . . . . . . . . .   16.5.3.6 Immunosuppressives  . . . . . . . . . . . . .   16.5.3.7 Psoralens  . . . . . . . . . . . . . . . . . . . . . . . .   16.5.3.8 Antiseptic Agents  .. . . . . . . . . . . . . . . .   16.5.3.9 Chelators  . . . . . . . . . . . . . . . . . . . . . . . .   16.5.3.10 Anti-glaucoma Agents  .. . . . . . . . . . .   16.5.3.11 Biologic Response Modifiers  . . . . . .   16.5.3.12 Paradoxical Hypertrichosis after Laser Epilation  . . . . . . . . . . . . . .   16.6 Treatment of Hypertrichosis  . . . . . .   Summary for the Clinician  .. . . . . . .  

XV

347 347 347 347 347 347 347 347 347 347 348 348 348 348 348 348 348 349 349 349 349 349 349 350 351 351 351 351 352 352 352 352 353 353 353 353 353

17

Hirsutism  .. . . . . . . . . . . . . . . . . . . . . . .   357 Francisco M. Camacho-Martínez

17.1 17.2 17.3 17.4

Introduction  . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Classification   . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .  

358 358 358 359

XVI

Contents

17.4.1 17.4.1.1 17.4.1.2 17.4.1.3 17.4.1.4 17.4.1.5 17.4.2 17.4.2.1 17.4.2.2 17.4.3 17.4.3.1 17.4.3.2 17.4.4 17.4.5 17.4.6 17.4.7 17.4.8 17.5 17.6 17.6.1 17.6.1.1 17.6.1.2 17.6.1.3 17.6.2 17.6.2.1 17.6.2.2 17.6.3 17.6.3.1

18

18.1 18.2

Constitutional or Dermatological Hirsutism (SAHA Syndrome)  . . . . .   Excess Ovarian Androgen Release Syndrome (Ovarian SAHA Syndrome)   . . . . . . . . . . . . . . . . . . . . . .   Persistent Adrenarche Syndrome (Adrenal SAHA Syndrome)  . . . . . . .   Hyperprolactinemic SAHA Syndrome  .. . . . . . . . . . . . . . . . . . . . . . .   Familial Hirsutism  .. . . . . . . . . . . . . . .   Familial Virilization (SAHA Type HAIRAN Syndrome)   .. . . . . . . . . . . .   Adrenal Hirsutism  .. . . . . . . . . . . . . . .   Non-Tumoral Adrenal Hirsutism  .   Tumoral Adrenal Hirsutism   . . . . . .   Ovarian Hirsutism  .. . . . . . . . . . . . . . .   Non-Tumoral Ovarian Hirsutism  .  Tumoral Ovarian Hirsutism  .. . . . . .   Pituitary or Hypophyseal Hirsutism  .. . . . . . . . . . . . . . . . . . . . . . .   Hepatic Hirsutism  .. . . . . . . . . . . . . . .   Iatrogenic Hirsutism  .. . . . . . . . . . . . .   Hirsutism due to Ectopic Hormones  . . . . . . . . . . . . . . . . . . . . . . .   Hirsutism due to the Alteration of the Peripheral Conversion of Androgens to Estrogens  . . . . . . . .   Diagnosis of Hirsutism  . . . . . . . . . . .   Treatment of Hirsutism  . . . . . . . . . . .   Systemic Treatment  .. . . . . . . . . . . . . .   Constitutional, Adrenal, Ovarian and Pituitary Hirsutism  .. . . . . . . . . .   Iatrogenic Hirsutism  .. . . . . . . . . . . . .   Other Types of Hirsutism  . . . . . . . . .   Topical Therapy  . . . . . . . . . . . . . . . . . .   Familial Hirsutism  .. . . . . . . . . . . . . . .   Hirsutism of SAHA Syndromes and Hyperandrogenisms  .. . . . . . . . .   Dermato-Cosmetical Therapy  . . . . .   Chemical and Physical Depilation  .   Summary for the Clinician  .. . . . . . .  

359 359 359 360 360 360 361 361 362 362 362 364 364 365 365 365 365 365 367 367 367 373 373 373 373 373 373 373 374

Scalp Tumors  .. . . . . . . . . . . . . . . . . . .   379 Antonella Tosti, Massimiliano Pazzaglia, Bianca Maria Piraccini

Introduction  . . . . . . . . . . . . . . . . . . . . .   Tumors of the Pilosebaceous Unit on the Scalp [22]  . . . . . . . . . . . . . . . . .   18.2.1 Trichoepithelioma  .. . . . . . . . . . . . . . .   18.2.1.1 Treatment Options  . . . . . . . . . . . . . . .   18.2.2 Pilomatrixoma  . . . . . . . . . . . . . . . . . . .   18.2.2.1 Treatment Options  . . . . . . . . . . . . . . .  

380 380 380 380 380 380

 

18.3 18.4 18.4.1 18.5 18.5.1 18.6 18.6.1 18.7 18.7.1 18.7.2 18.7.3 18.8 18.8.1 18.9 18.9.1 18.9.2 18.9.3 18.9.4 18.9.5 18.9.6 18.9.7 18.10 18.10.1 18.11 18.11.1 18.11.2 18.11.3 18.12 18.13

Sebaceous Nevus  . . . . . . . . . . . . . . . . .   Actinic Keratosis  . . . . . . . . . . . . . . . . .   Treatment Options  . . . . . . . . . . . . . . .   Basal Cell Carcinoma  .. . . . . . . . . . . .   Treatment Options  . . . . . . . . . . . . . . .   Squamous Cell Carcinoma  . . . . . . . .   Treatment Options  . . . . . . . . . . . . . . .   Primary Melanoma of the Scalp  . . .   Lentigo Maligna  .. . . . . . . . . . . . . . . . .   Desmoplastic Melanoma  .. . . . . . . . .   Treatment Options  . . . . . . . . . . . . . . .   Angiosarcoma  .. . . . . . . . . . . . . . . . . . .   Treatment Options  . . . . . . . . . . . . . . .   Scalp Metastases  .. . . . . . . . . . . . . . . . .   Scalp Metastases from Lung Cancer   . . . . . . . . . . . . . . . . . . . . . . . . . .   Scalp Metastases from Breast Cancer   . . . . . . . . . . . . . . . . . . . . . . . . . .   Scalp Metastases from Colon Cancer   . . . . . . . . . . . . . . . . . . . . . . . . . .   Scalp Metastases from Gastric Cancer   . . . . . . . . . . . . . . . . . . . . . . . . . .   Scalp Metastases from Renal Cancer   . . . . . . . . . . . . . . . . . . . . . . . . . .   Scalp Metastases from Esophageal Carcinoma   . . . . . . . . . . . . . . . . . . . . . .   Treatment Options  . . . . . . . . . . . . . . .   Metastatic Carcinoma of the Scalp  .  Treatment Options  . . . . . . . . . . . . . . .   Lymphomas  .. . . . . . . . . . . . . . . . . . . . .   Non-Hodgkin’s Lymphomas  .. . . . . .   Mycosis Fungoides, Follicular Mycosis Fungoides and Sézary Syndrome  .. . . . . . . . . . . . . . . . . . . . . . .   Follicular Mucinosis  .. . . . . . . . . . . . .   Scalp Hemangiomas  . . . . . . . . . . . . . .   Epidermoid Cyst  . . . . . . . . . . . . . . . . .   Summary for the Clinician  .. . . . . . .  

381 381 382 382 382 383 383 383 384 384 384 384 384 384 385 385 385 385 385 385 385 385 385 386 386 386 386 387 387 387

19

Disorders of the Scalp  .. . . . . . . . . .   389 Rodney Sinclair, Yee Jen Tai

19.1 19.1.1 19.1.2 19.1.3 19.1.4 19.1.5 19.1.6 19.1.7 19.1.8 19.2 19.2.1

Tinea Capitis  .. . . . . . . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Pediculosis Capitis  .. . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .  

390 390 390 390 390 390 391 391 391 392 392

Contents

19.2.2 19.2.3 19.2.4 19.2.5 19.2.6 19.2.7 19.2.8 19.3 19.3.1 19.3.2 19.3.3 19.3.4 19.3.5 19.3.6 19.3.7 19.3.8 19.4 19.4.1 19.4.2 19.4.3 19.4.4 19.4.5 19.4.6 19.4.7 19.4.8 19.5 19.5.1 19.5.2 19.5.3 19.5.4 19.5.5 19.5.6 19.5.7 19.5.8 19.6 19.6.1 19.6.2 19.6.3 19.6.4 19.6.5 19.6.6 19.6.7 19.6.8 19.7 19.7.1 19.7.2 19.7.3 19.7.4 19.7.5 19.7.6 19.7.7 19.8 19.8.1

History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Seborrheic Dermatitis  . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Psoriasis  . . . . . . . . . . . . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Atopic Dermatitis of the Scalp and Lichen Simplex Chronicus  . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Contact Dermatitis  . . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Pustular Conditions of the Scalp  .. .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Pruritus and Burning of the Scalp  .  Introduction  . . . . . . . . . . . . . . . . . . . . .  

392 392 392 393 393 393 393 394 394 394 394 394 394 395 395 395 396 396 396 396 396 396 397 397 397 398 398 398 398 398 398 399 399 399 399 399 399 399 400 400 400 400 401 401 401 401 401 401 401 402 402 402 402

19.8.2 19.8.3 19.8.4 19.8.5

Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features and Differential Diagnosis  . . . . . . . . . . . . . . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Summary for the Clinician  .. . . . . . .  

XVII

402 402 402 403 403

20

Psychocutaneous Disorders of Hair and Scalp  . . . . . . . . . . . . . . . .   407 Ralph M. Trüeb, Uwe Gieler

20.1 20.2 20.3 20.4

Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Categorizing Psychocutaneous Disorders  . . . . . . . . . . . . . . . . . . . . . . . .   Underlying Psychopathologic Conditions  .. . . . . . . . . . . . . . . . . . . . . .   Psychophysiological Disorders  . . . .   Primary Psychiatric Disorders  .. . . .   Generalized Anxiety Disorder  .. . . .   Depressive Disorder  . . . . . . . . . . . . . .   Delusional Disorder  . . . . . . . . . . . . . .   Obsessive-Compulsive Disorder  .. .   Cutaneous Sensory Disorders  . . . . .   Conversion Disorder  . . . . . . . . . . . . .   Hypochondriacal Disorder and Body Dysmorphic Disorder  .. .   Somatization Disorder  .. . . . . . . . . . .   Somatoform Pain Disorder  .. . . . . . .   Secondary Psychiatric Disorders  .. .   Dermatologic Presentations  .. . . . . .   Trichotillomania  . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Prognosis  . . . . . . . . . . . . . . . . . . . . . . . .   Neurotic Scalp Excoriations   . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Prognosis  . . . . . . . . . . . . . . . . . . . . . . . .   Factitial Dermatitis of the Scalp  . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Prognosis  . . . . . . . . . . . . . . . . . . . . . . . .   Delusions of Parasitosis  .. . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .  

20.5 20.5.1 20.5.2 20.5.2.1 20.5.2.2 20.5.2.3 20.5.2.4 20.5.3 20.5.3.1 20.5.3.2 20.5.3.3 20.5.3.4 20.5.4 20.6 20.6.1 20.6.1.1 20.6.1.2 20.6.1.3 20.6.1.4 20.6.1.5 20.6.2 20.6.2.1 20.6.2.2 20.6.2.3 20.6.2.4 20.6.2.5 20.6.3 20.6.3.1 20.6.3.2 20.6.3.3 20.6.3.4 20.6.3.5 20.6.4 20.6.4.1 20.6.4.2

408 408 409 409 410 410 410 411 411 411 412 412 412 413 413 413 414 414 414 414 415 415 416 417 417 417 417 417 418 419 419 419 420 420 420 421 421 421 421

XVIII

Contents

20.6.4.3 20.6.4.4 20.6.4.5 20.6.5 20.6.5.1 20.6.5.2 20.6.5.3 20.6.5.4 20.6.5.5 20.6.6 20.6.6.1 20.6.6.2 20.6.6.3 20.6.6.4 20.6.6.5

Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Prognosis  . . . . . . . . . . . . . . . . . . . . . . . .   Scalp Dysesthesia  .. . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Prognosis  . . . . . . . . . . . . . . . . . . . . . . . .   Psychogenic Pseudoeffluvium  . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Prognosis  . . . . . . . . . . . . . . . . . . . . . . . .   Summary for the Clinician  .. . . . . . .  

21

Photoepilation  . . . . . . . . . . . . . . . . . .   427 Christine C. Dierickx

21.1 21.2 21.3 21.3.1

Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Technology  . . . . . . . . . . . . . . . . . . . . . .   Mechanisms of Hair Follicle Destruction  . . . . . . . . . . . . . . . . . . . . . .   Photothermal Destruction  . . . . . . . .   Photomechanical Destruction  .. . . .   Photochemical Destruction  . . . . . . .   Treatment Approach  .. . . . . . . . . . . . .   Patient History  .. . . . . . . . . . . . . . . . . .   Physical Examination  .. . . . . . . . . . . .   Preoperative Care  . . . . . . . . . . . . . . . .   Six Weeks before Laser Treatment  .   Day before Laser Treatment.  . . . . . .   Day of Treatment   . . . . . . . . . . . . . . . .   Laser and Light Source Selection  . .   Endogenous Chromophore  .. . . . . . .   Exogenous Chromophore  .. . . . . . . .   Treatment Technique  . . . . . . . . . . . . .   Post-Operative Considerations   .. . .   Subsequent Treatments  . . . . . . . . . . .   Expected Benefits  .. . . . . . . . . . . . . . . .   Side-Effects and Managements of Complications  . . . . . . . . . . . . . . . . .   Future Directions  .. . . . . . . . . . . . . . . .   Summary for the Clinician  .. . . . . . .  

21.3.2 21.3.3 21.3.4 21.4 21.4.1 21.4.2 21.4.3 21.4.3.1 21.4.3.2 21.4.3.3 21.4.4 21.4.4.1 21.4.4.2 21.4.5 21.4.6 21.5 21.5.1 21.5.2 21.6

421 422 422 422 422 422 423 423 423 423 423 423 424 424 425 425

428 428 428 428 428 429 429 429 430 430 431 431 431 431 431 431 438 439 439 439 439 442 443 444

22

Surgical Treatment of Hair Loss  .  447 Walter P. Unger, Robin H. Unger

22.1 22.2 22.3

Introduction  . . . . . . . . . . . . . . . . . . . . .   448 History  . . . . . . . . . . . . . . . . . . . . . . . . . .   448 Technology  . . . . . . . . . . . . . . . . . . . . . .   448

 

22.3.1 22.3.1.1 22.3.1.2 22.3.1.3 22.3.1.4 22.3.2

Planning  .. . . . . . . . . . . . . . . . . . . . . . . .   Male Patients  .. . . . . . . . . . . . . . . . . . . .   Female Patients  .. . . . . . . . . . . . . . . . . .   The Hairline  .. . . . . . . . . . . . . . . . . . . . .   Alopecia Reduction  .. . . . . . . . . . . . . .   Preoperative Instructions and Anesthesia  .. . . . . . . . . . . . . . . . . .   22.3.3 The Donor Site  . . . . . . . . . . . . . . . . . . .   22.3.4 Graft Preparation  .. . . . . . . . . . . . . . . .   22.3.5 The Recipient Area  . . . . . . . . . . . . . . .   22.3.5.1 Follicular Unit Hair Transplanting (FUT)  . . . . . . . . . . . . . . . . . . . . . . . . . . .   22.3.5.2 FUT Combined with MUGs  .. . . . . .   22.3.5.3 Hair Restoration Surgery in the Vertex Area  . . . . . . . . . . . . . . . .   22.3.6 Insertion of Grafts  .. . . . . . . . . . . . . . .   22.3.7 Bandaging and Postoperative Care  .  22.3.8 Postoperative Course and Complications  . . . . . . . . . . . . . . .   22.3.9 Alopecia Reduction   . . . . . . . . . . . . . .   22.3.10 Flap Surgery  . . . . . . . . . . . . . . . . . . . . .   22.3.11 Cicatricial Alopecia   . . . . . . . . . . . . . .   Summary for the Clinician  .. . . . . . .  

448 448 451 452 453 454 455 456 457 458 459 460 461 462 462 463 463 463 463

23

Tropical Dermatoses of the Scalp  . . . . . . . . . . . . . . . . . . . . .   467 Mohsen Soliman, Hiram Larangeira de Almeida Jr.

23.1 23.1.1 23.1.1.1 23.1.1.2 23.1.1.3 23.1.1.4 23.1.1.5 23.1.2 23.1.2.1 23.1.2.2

Bacterial Infections of the Scalp  . . .   Pyodermas  .. . . . . . . . . . . . . . . . . . . . . .   Introduction   .. . . . . . . . . . . . . . . . . . . .   Epidemiology   .. . . . . . . . . . . . . . . . . . .   Clinical Features   .. . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Tuberculosis Cutis  .. . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   Classification of Cutaneous Tuberculosis  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Differential Diagnosis   .. . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Leprosy  .. . . . . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Introduction   .. . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Presentation  . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Histopathology  .. . . . . . . . . . . . . . . . . .  

23.1.2.3 23.1.2.4 23.1.2.5 23.1.2.6 23.1.2.7 23.1.2.8 23.1.3 23.1.3.1 23.1.3.2 23.1.3.3 23.1.3.4 23.1.3.5 23.1.3.6 23.1.3.7

467 467 468 468 468 469 469 469 470 470 470 470 470 471 471 471 472 472 472 472 472 472 473 473

Contents

23.1.3.8 23.1.4 23.1.4.1 23.1.4.2 23.1.4.3 23.1.4.4 23.1.4.5 23.1.4.6 23.1.4.7 23.1.5 23.1.5.1 23.1.5.2 23.1.5.3 23.1.5.4 23.1.5.5 23.1.5.6 23.1.5.7 23.1.6 23.1.6.1 23.1.6.2 23.2 23.2.1 23.2.1.1 23.2.1.2 23.2.1.3 23.2.1.4

Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Syphilis  .. . . . . . . . . . . . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History   .. . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology   .. . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Laboratory Examination  . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Deep Mycosis and Leishmaniosis  .  Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Pathogenesis   .. . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology   . . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis   .. . . . . . . . . . .   Treatment   . . . . . . . . . . . . . . . . . . . . . . .   Piedras  . . . . . . . . . . . . . . . . . . . . . . . . . .   White Piedra  .. . . . . . . . . . . . . . . . . . . .   Black Piedra  .. . . . . . . . . . . . . . . . . . . . .   Nutritional Disorders  .. . . . . . . . . . . .   Pellagra  .. . . . . . . . . . . . . . . . . . . . . . . . .   Introduction   .. . . . . . . . . . . . . . . . . . . .   Clinical Presentation  . . . . . . . . . . . . .   Differential Diagnosis   .. . . . . . . . . . .   Treatment   . . . . . . . . . . . . . . . . . . . . . . .   Summary for the Clinician  .. . . . . . .  

24

African Hair  . . . . . . . . . . . . . . . . . . . . .   483 Nonhlanhla P. Khumalo, Valerie D. Callender

24.1 24.2 24.3

Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Structure and Function/ Pathophysiology/Developments  . . .   Experimental Techniques  . . . . . . . . .   Clinical Relevance   . . . . . . . . . . . . . . .   Outlook – Future Developments  .. .   Dissecting Cellulitis  . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Acne Keloidalis Nuchae  .. . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .  

24.4 24.5 24.6 24.7 24.7.1 24.7.2 24.7.3 24.7.4 24.7.5 24.7.6 24.7.7 24.7.8 24.8 24.8.1 24.8.2 24.8.3 24.8.4 24.8.5

473 474 474 474 474 474 474 474 475 475 476 476 476 476 476 477 477 477 477 478 479 479 480 480 480 480 480

24.8.6 24.8.7 24.8.8 24.9 24.9.1 24.9.2 24.9.3 24.9.4 24.9.5 24.9.6 24.9.7 24.9.8 24.10 24.10.1 24.10.2 24.10.3 24.10.4 24.10.5 24.10.6 24.10.7 24.10.8 24.11 24.11.1 24.11.2 24.11.3 24.11.4 24.11.5 24.11.6 24.11.7 24.11.8

Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Central Centrifugal Cicatricial Alopecia  . . . . . . . . . . . . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment   . . . . . . . . . . . . . . . . . . . . . . .   Traction Alopecia  . . . . . . . . . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology  .. . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Pseudofolliculitis Barbae  .. . . . . . . . .   Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Epidemiology  . . . . . . . . . . . . . . . . . . . .   Pathogenesis  . . . . . . . . . . . . . . . . . . . . .   Clinical Features  . . . . . . . . . . . . . . . . .   Pathology   . . . . . . . . . . . . . . . . . . . . . . .   Differential Diagnosis  .. . . . . . . . . . . .   Treatment  .. . . . . . . . . . . . . . . . . . . . . . .   Summary for the Clinician   . . . . . . .  

XIX

489 490 490 490 490 490 491 491 491 491 491 491 492 492 492 492 492 492 492 492 493 493 494 494 494 494 494 494 494 494 495

484 484

25

484 485 485 486 486 486 486 487 487 487 487 488 488 488 488 488 488 489 489

Hair Cosmetics  . . . . . . . . . . . . . . . . . .   499 Zoe Diana Draelos

25.1 25.2 25.2.1 25.2.2 25.2.3 25.2.4 25.2.5 25.3 25.3.1 25.3.2 25.4 25.4.1 25.4.1.1 25.4.1.2 25.4.1.3 25.4.1.4 25.4.1.5 25.4.1.6

Introduction  . . . . . . . . . . . . . . . . . . . . .   Shampoos  .. . . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Technology  . . . . . . . . . . . . . . . . . . . . . .   Anionic Detergents  .. . . . . . . . . . . . . .   Nonionic Detergents  .. . . . . . . . . . . . .   Amphoteric Detergents  . . . . . . . . . . .   Conditioners  .. . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Technology  . . . . . . . . . . . . . . . . . . . . . .   Styling Aids  .. . . . . . . . . . . . . . . . . . . . .   Technology  . . . . . . . . . . . . . . . . . . . . . .   Spray  . . . . . . . . . . . . . . . . . . . . . . . . . . . .   Gel  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   Wax  . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   Mousse  . . . . . . . . . . . . . . . . . . . . . . . . . .   Pomade  .. . . . . . . . . . . . . . . . . . . . . . . . .   Brilliantine  .. . . . . . . . . . . . . . . . . . . . . .  

500 500 500 500 500 502 502 502 502 503 503 503 503 504 504 504 505 505

XX

Contents

25.4.1.7 25.4.1.8 25.5 25.5.1 25.5.2 25.5.3 25.5.4 25.5.5 25.5.6 25.6 25.6.1 25.6.2 25.6.3 25.6.4 25.6.5 25.6.6 25.6.7 25.6.8 25.7 25.7.1 25.7.2

26

26.1 26.2 26.2.1 26.2.1.1 26.2.1.2 26.2.1.3 26.2.1.4 26.2.1.5 26.2.1.6 26.2.1.7 26.2.1.8 26.2.1.9 26.2.1.10 26.2.1.11 26.2.1.12 26.2.1.13 26.3 26.3.1 26.3.2

Oil Sheen Spray  . . . . . . . . . . . . . . . . . .   Gel Curl Activator  .. . . . . . . . . . . . . . .   Dyeing  .. . . . . . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Technology  . . . . . . . . . . . . . . . . . . . . . .   Gradual  .. . . . . . . . . . . . . . . . . . . . . . . . .   Temporary  .. . . . . . . . . . . . . . . . . . . . . .   Semipermanent  . . . . . . . . . . . . . . . . . .   Permanent  . . . . . . . . . . . . . . . . . . . . . . .   Permanent Waving  . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Technology  . . . . . . . . . . . . . . . . . . . . . .   Alkaline Permanent Waves  .. . . . . . .   Buffered Alkaline Permanent Waves  . . . . . . . . . . . . . . . . . . . . . . . . . . .   Exothermic Permanent Waves  .. . . .   Self-Regulated Permanent Waves  .   Acid Permanent Waves  . . . . . . . . . . .   Sulfite Permanent Waves  .. . . . . . . . .   Permanent Hair Straightening  .. . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Technology  . . . . . . . . . . . . . . . . . . . . . .   Summary for the Clinician   . . . . . . .  

505 505 505 505 505 506 507 507 507 508 508 508 509 510 510 510 510 510 510 510 511 512

Natural Products for Hair Care and Treatment  . . . . . . . . . . . . .   515 Wilma F. Bergfeld, F. Alan Andersen Natural Products for Hair Care and Treatment  .. . . . . . . . . . . . . . . . . . .   Important Natural Ingredients that Possibly Promote Hair Growth  . . . . . . . . . . . . . . . . . . . . .   Hair Promoters  .. . . . . . . . . . . . . . . . . .   Asiasari   . . . . . . . . . . . . . . . . . . . . . . . . .   Proanthocyanidins  . . . . . . . . . . . . . . .   Ginkgo Biloba  .. . . . . . . . . . . . . . . . . . .   Aloe  .. . . . . . . . . . . . . . . . . . . . . . . . . . . .   Proteins  .. . . . . . . . . . . . . . . . . . . . . . . . .   Bergamot   .. . . . . . . . . . . . . . . . . . . . . . .   Chinese Herb  . . . . . . . . . . . . . . . . . . . .   Ginseng  .. . . . . . . . . . . . . . . . . . . . . . . . .   Henna  . . . . . . . . . . . . . . . . . . . . . . . . . . .   Hibiscus Extract  .. . . . . . . . . . . . . . . . .   Hydrangea  . . . . . . . . . . . . . . . . . . . . . . .   Illicium  .. . . . . . . . . . . . . . . . . . . . . . . . .   Sorphora   . . . . . . . . . . . . . . . . . . . . . . . .   Natural Hair Growth Promoters with DHT Inhibitory Activity   .. . . .   Natural Fatty Acids with DHT Inhibition  .. . . . . . . . . . . . . . . . . . . . . . .   Saw Palmetto  .. . . . . . . . . . . . . . . . . . . .  

516 518 518 518 518 518 518 519 519 519 519 519 519 519 520 520

 

26.4 26.5 26.5.1 26.6 26.6.1 26.7 26.7.1 26.7.2 26.7.3 26.7.4 26.7.5 26.7.6 26.8 26.9

Natural Ingredients that Retard Hair Growth  . . . . . . . . . . . . . . . . . . . . .   Natural Hair Conditioning – Repair of Damaged Hair  . . . . . . . . . .   Oligosaccharides  . . . . . . . . . . . . . . . . .   Natural Hair Color  . . . . . . . . . . . . . . .   Henna  . . . . . . . . . . . . . . . . . . . . . . . . . . .   Natural Ingredients for the Treatment of Seborrheic Dermatitis   .. . . . . . . . . . . . . . . . . . . . . .   Sage  . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   Rosemary  .. . . . . . . . . . . . . . . . . . . . . . .   Thyme  .. . . . . . . . . . . . . . . . . . . . . . . . . .   Garlic  .. . . . . . . . . . . . . . . . . . . . . . . . . . .   Walnut  .. . . . . . . . . . . . . . . . . . . . . . . . . .   Tea Tree Oil  .. . . . . . . . . . . . . . . . . . . . .   Natural Ingredients for the Treatment of Lice   . . . . . . . . .   Contact Dermatitis  . . . . . . . . . . . . . . .   Summary for the Clinician  .. . . . . . .  

520 520 521 521 521 521 521 521 522 522 522 522 522 522 523

27

Hair over the Ages and in Art – The Culture, and Social History of Hair and its Depiction in Art  . .   525 Norbert Haas

27.1 27.2 27.3

Introduction  . . . . . . . . . . . . . . . . . . . . .   Ancient World  . . . . . . . . . . . . . . . . . . .   Hairstyles in Greek and Roman Antiquity  .. . . . . . . . . . . .   The Middle Ages in the Western World  .. . . . . . . . . . . .   Renaissance Europe  . . . . . . . . . . . . . .   The Wig’s Century  .. . . . . . . . . . . . . . .   From the Nineteenth to the Twenty-First Century  .. . . . . .   Hairstyles in Non-European Cultures  . . . . . . . . . . . . . . . . . . . . . . . . .   Conclusion  .. . . . . . . . . . . . . . . . . . . . . .  

27.4 27.5 27.6 27.7 27.8 27.9

525 525 526 529 531 532 533 534 536

28

Hair in Forensic Medicine  .. . . . . . .   539 Bianca Maria Piraccini, Massimiliano Pazzaglia, Antonella Tosti

520

28.1 28.2 28.3

520 520

28.4 28.4.1

Introduction  . . . . . . . . . . . . . . . . . . . . .   History  . . . . . . . . . . . . . . . . . . . . . . . . . .   Pathophysiology of Incorporation of Substances into Hair  . . . . . . . . . . .   Techniques of Analysis [8, 9]  .. . . . .   Hair Sampling  .. . . . . . . . . . . . . . . . . . .  

539 540 540 541 541

Contents

28.4.2

Decontamination, Extraction, and Detection  .. . . . . . . . . . . . . . . . . . .   28.5 Clinical Interpretation  . . . . . . . . . . . .   28.6 Purposes of Hair Analysis  .. . . . . . . .   28.6.1 Forensic Investigations  .. . . . . . . . . . .   28.6.1.1 Drug Abuse and Poisoning  .. . . . . . .   28.6.1.2 Rape Cases  .. . . . . . . . . . . . . . . . . . . . . .   28.6.2 Doping Controls  . . . . . . . . . . . . . . . . .   28.6.3 Occupational Medicine  . . . . . . . . . . .  

541 541 541 541 541 541 541 541

28.6.4 28.6.5 28.7

Prenatal Exposure  . . . . . . . . . . . . . . . .   Patient’s Compliance to Drug Prescription  .. . . . . . . . . . . . . . . . . . . . .   Future Developments  .. . . . . . . . . . . .   Summary for the Clinician   . . . . . . .  

XXI

542 542 542 542

Subject Index  .. . . . . . . . . . . . . . . . . . . . . . . . . . . . .   543

Contributors

Hiram Larangeira de Almeida Jr Associate Professor of Dermatology Federal University of Pelotas Av. Duque de Caxias 250 96.030-002 Pelotas Brazil F. Alan Andersen Director, Cosmetic Ingredient Review 1101 17th Street NW, Suite 412 Washington DC USA Wilma F. Bergfeld FACP Cleveland Clinic Departments of Dermatology and Pathology 9500 Euclid Avenue, A61 Cleveland, OH 44195 USA Ulrike Blume-Peytavi Clinical Research Center for Hair and Skin Science (CRC) Department of Dermatology and Allergy Charité – Universitätsmedizin Berlin Charitéplatz 1 10117 Berlin Germany Vladimir A. Botchkarev Professor of Cutaneous Biology Division of Biomedical Science School of Life Science Richmond Road, Bradford West Yorkshire BD71DP UK

Valerie D. Callender Skin and Laser Center Suite 225 Mitchellville, MD 20721 USA Francisco M. Camacho-Martίnez Department of Dermatology Hospital Universitario Virgen Macarena 41009 Sevilla Spain Angela M. Christiano Department of Dermatology and Genetics & Development Columbia University College of Physicians and Surgeons 630 West 168th Street New York, NY 10032 USA Christine C. Dierickx Director Skin and Laser Surgery Center Beukenlaan 52 2850 Boom Antwerp Belgium

XXIV

Contributors

Zoe D. Draelos Clinical Associate Professor Department of Dermatology Wake Forest University School of Medicine Winston-Salem, North Carolina USA and Dermatology Consulting Services 2444 North Main Street High Point, NC 27262 North Carolina USA Marna Ericson Department of Dermatology University of Minnesota MMC 98 420 Delaware St. SE MN 55455 Minneapolis USA Andreas M. Finner Trichomed- Praxis für Haarmedizin und Haartransplantation Klinik am Wittenbergplatz Bayreuther Str. 36 10789 Berlin Germany Pia Freyschmidt-Paul Schimmelpfengstr. 4 34613 Schwalmstadt Germany Natalie Garcia Bartels Clinical Research Center for Hair and Skin Science (CRC) Department of Dermatology and Allergy Charité – Universitätsmedizin Berlin Charitéplatz 1 10117 Berlin Germany Uwe Gieler Klinik für Psychosomatik und Psychotherapie Universitätsklinikum Giessen und Marburg GmbH Standort Giessen Ludwigstrasse 76 35392 Giessen Germany

 

Marcella Guarrera DiSEM, Section of Dermatology University of Genoa Viale Benedetto XV, n.7 16132, Genova Italy Norbert Haas Department of Dermatology and Allergy Charité – Universitätsmedizin Berlin Charitéplatz 1 10117 Berlin Germany Kathrin Hillmann Clinical Research Center for Hair and Skin Science (CRC) Department of Dermatology and Allergy Charité – Universitätsmedizin Berlin Charitéplatz 1 10117 Berlin Germany Rolf Hoffmann Kaiser-Joseph-Str. 262 79098 Freiburg Germany Maria Hordinsky Department of Dermatology University of Minnesota MMC 98 420 Delaware St. SE MN 55455 Minneapolis USA Nonhlanhla P. Khumalo Division of Dermatology Ward G23 Groote Schuur Hospital and The University of Cape Town Observatory, 7925 Cape Town South Africa Kevin J. McElwee Division of Dermatology University of British Columbia 835 West 10th Avenue Vancouver B.C. Canada

Contributors

Andrew Messenger Department of Dermatology Royal Hallamshire Hospital Glossop Road Sheffield, S10 2JF UK Elise A. Olsen Division Dermatology and Oncology Duke University Medical Center Box 3294 DUMC Durham, NC 27710 USA Massimiliano Pazzaglia Department of Dermatology University of Bologna Via Massarenti 1 40138 Bologna Italy Eva M.J. Peters Cutaneous Neuroimmunology Internal Medicine-Psychosomatics Charité – Universitätsmedizin 10117 Berlin Germany Bianca M. Piraccini Department of Dermatology University of Bologna Via Massarenti 1 40138 Bologna Italy Valerie A. Randall Division of Biomedical Sciences University of Bradford Richmond Road, Bradford West Yorkshire BD71DP UK

Yutaka Shimomura Departments of Dermatology and Genetics & Development Columbia University College of Physicians and Surgeons 630 West 168th Street New York, NY 10032 USA Rodney Sinclair Senior Lecturer, Department of Dermatology University of Melbourne St. Vincent’s Hospital PO Box 2900 Fitzroy, Victoria 3065 Australia Mohsen Soliman Professor of Dermatology Faculty of Medicine Cairo University 11, El-Falaky Square Bab Ellouk, Cairo Egypt Yee Jen Tai Registrar Department of Dermatology Services, St. Vincent’s Hospital Melbourne PO Box 2900 Fitzroy 3065 Australia Desmond J. Tobin Professor of Cell Biology Director of SLS Medical Biosciences Res. Focus Grp. School of Life Sciences University of Bradford Richmond Road, Bradford West Yorkshire BD71DP UK

Elizabeth K. Ross 4337 W. 14th Ave. Vancouver, British Columbia V6R 2X9 Canada

Antonella Tosti Department of Dermatology University of Bologa Via Massarenti 1 40138 Bologna Italy

Jerry Shapiro University of British Columbia Hair Research and Treatment Center 835 West. 10th Avenue Vancouver, British Columbia V5Z 4E8 Canada

Ralph M. Trüeb Department of Dermatology University Hospital of Zürich Gloriastrasse 31 8091 Zürich Switzerland

XXV

XXVI

Contributors

Walter P. Unger Mount Sinai School of Medicine, New York 99 Yorkville Ave. Suite 214 Toronto ON, M5R 3K5 Canada and 620 Park Avenue New York NY  10065 USA Robin H. Unger 620 Park Avenue New York, NY 10021 USA

 

Annika Vogt Clinical Research Center for Hair and Skin Science (CRC) Department of Dermatology and Allergy Charité – Universitätsmedizin Berlin Charitéplatz 1 10117 Berlin Germany David A. Whiting The Hair and Skin Research and Treatment Center 3600 Gaston Avenue Suite 1058, Wadley Tower Dallas, TX 75246 USA Abraham Zlotogorski Department of Dermatology Hadassah-Hebrew University Medical Center Jerusalem 91120 Israel

Chapter 1

Biology of the Hair Follicle Annika Vogt, Kevin J. McElwee, Ulrike Blume-Peytavi

1

Contents 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.7.1 1.7.2 1.7.3 1.7.4 1.8 1.8.1 1.8.2 1.8.3 1.8.4 1.8.5

1.1

Introduction  . . . . . . . . . . . . . . . . . . . . . . . . . . History  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hair Follicle Morphogenesis  . . . . . . . . . . . . Molecular Mediation of Hair Follicle Morphogenesis  . . . . . . . . . . . . . . . . . . . . . . . Anatomy of the Mature Pilosebaceous Unit  . . . . . . . . . . . . . . . . . . . . Hair Fiber Properties  . . . . . . . . . . . . . . . . . . Hair Follicle Types  . . . . . . . . . . . . . . . . . . . . . Lanugo Hair  . . . . . . . . . . . . . . . . . . . . . . . . . . Vellus Hair  . . . . . . . . . . . . . . . . . . . . . . . . . . . Intermediate Hair  . . . . . . . . . . . . . . . . . . . . . Terminal Hair  . . . . . . . . . . . . . . . . . . . . . . . . Hair Cycling  . . . . . . . . . . . . . . . . . . . . . . . . . . Anagen  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Catagen  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Telogen  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Exogen  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kenogen   . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

 1  1  2  3  5  6  9  9  9   10   10   10   11   12   12   12   12

Introduction

Over the last few decades, progress in molecular biology and genetics, as well as the development of new experimental approaches, has brought together scientists from all fields. Developmental biologists, geneticists, endocrinologists, and dermatologists now study the many diverse facets of hair follicle biology including neuroectodermal–mesenchymal interactions, immunology, pigmentation, and stem cell biology. In humans, the main function of the hair shaft is its role as an important facet of appearance. Across cultures for centuries, the decoration and styling of scalp hair has been a means of social communication and display of social identity or status. Hair is so important in our society that hair loss, as well as the overgrowth of terminal hair on the body or face, has deleterious effects on self-esteem. The clinical relevance of hair and hair growth impairment goes far beyond the diagnosis and treatment of hair disorders, as the following examples illustrate. More than 300 genetic conditions have hair abnormali-

1.8.6 1.8.7 1.8.8

1.9 1.10 1.10.1 1.10.2 1.10.3 1.10.4 1.11 1.12 1.13

Duration of the Hair Cycle   . . . . . . . . . . . . . Hair Growth and Cycle Regulation Potential of the Dermal Papilla  . . . . . . . . . . Developmental Pathways, Cytokines, Growth Factors, and Neuroendocrine Factors  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hair Growth Changes with Age  . . . . . . . . . . Specialized Hair Follicle Compartments  . . Stem Cells  . . . . . . . . . . . . . . . . . . . . . . . . . . . . Immunology  . . . . . . . . . . . . . . . . . . . . . . . . . Neuroimmunological and Neuroendocrine Interactions   . . . . . . . Melanocytes  . . . . . . . . . . . . . . . . . . . . . . . . . . Experimental Techniques  . . . . . . . . . . . . . . . Clinical Relevance  . . . . . . . . . . . . . . . . . . . . . Outlook – Future Developments  . . . . . . . . . Summary for the Clinician   . . . . . . . . . . . . .

  12   13

  13   14   15   15   16   17   17   17   18   19   19

References   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   20 ties as a component feature, and so the evaluation of hair growth is an easy, first-level diagnostic tool in pediatric dermatology and genetics. Identifying hair abnormalities can also be a useful aid in the diagnosis of suspected defects and diseases in their early stages, before more severe symptoms of progressive multi-organ involvement develop. As hair is continuously shed and allows for non-invasive collection, it can also be an important component of evidence in forensic medicine. Finally, drugs, chemicals, and biological substances accumulate and are stored in hair fiber where they can be detected and measured.

1.2

History

In the fourth century BC the philosopher Aristotle suggested that hair formed from sooty vapors exhaled through the body’s pores that hardened on contact with air. These vapors were residues that the body was unable to dispose of through concoction, the process whereby food was made into nourishment (blood) for the body.

2

A. Vogt, K. J. McElwee, U. Blume-Peytavi

  Fig. 1.1.  Morphogenesis of the human hair follicle. Hair follicle formation is the result of complex sequential signaling events between the dermal mesenchyme and the overlying epithelium. Morphologically, induction, organogenesis, and cytodifferentiation phases can be determined

1

In the eleventh century AD, Saint and scientist Albertus Magnus, unable to determine a special role for the hair, assigned it an excretory function, and believed that scalp hair fiber was the product of gross humor and phlegm divested from the brain. Early in the sixteenth century, a microscopic study of mouse hair fiber allowed scientist William Derham to see medullae and led him to suggest the hair fibers were tubules for the evacuation of humor and perspiration from the body [18]. With the development of histological tissue analysis it became clear that hair fiber was rooted deep in the skin “implanted in the pyramidal papillae,” through which the hairs were thought to imbibe nourishment from the adjacent humors [10]. Only with the careful study of the skin and hair follicles by anatomists in the nineteenth century were hair follicle structure and its embryogenesis fully defined, and the mechanism of hair fiber growth correctly extrapolated [88]. Recent advances in molecular biology and genetics have revolutionized our understanding of hair cycling and hair growth. In particular, an increasing number of spontaneous or experimentally generated murine mutations have provided valuable insights into the functional significance of selected gene products in hair follicle morphogenesis and cycling. The identification of animal models of human diseases has helped to evaluate the relevance of candidate gene approaches.

1.3

Hair Follicle Morphogenesis

Hair follicle appendage formation involves a complex sequence of signals between the dermal mesenchyme and the overlying epithelium. The precise initiating stimulus is still to be defined. Morphologically, induction, organogenesis and cytodifferentiation phases can be determined, and a division of hair follicle formation events into eight distinct developmental stages in rodents and humans can be made [75]. The development of human hair follicles first starts between the 8th and 12th weeks of gestation. Probably in response to dermal signaling elements, which are expressed in gradients over the developing fetus, thickening of the primitive epithelium forms placodes that induce the aggregation

of underlying dermal cells to mesenchymal condensates [19] – the first visible stage in hair follicle development (Fig. 1.1). The very first hair follicle placodes are seen in the eyebrow, upper lip, and chin regions. Placode formation subsequently expands in a wave caudally and ventrally over the skin of the fetus. The dermal condensates issue instructions to the cells of their associated overlying ectodermal placodes to proliferate and initiate penetration of the dermis; stage 2 of development. As the epithelial cells grow downwards into the dermis, the dermal condensate cells lead the way. The hair follicles grow into the dermis at an angle to the skin surface, with the degree of angle determined by the location of the hair follicle [66]. The initial placode formation stage gives way to an early peg stage (stage 3) hair follicle. By 12–14 weeks’ gestation, the epithelial base of the hair pegs on the scalp invaginates to envelop the dermal cell condensates and form dermal papillae. This stage of development is described as the bulbous hair peg stage, or stage 4 in development [28]. In stage 5 at 13–16 weeks’ gestation, the superficial portions of the hair follicles subsequently develop two distinct, asymmetrical bulges of cells on the “posterior” side of the follicle, which is at an obtuse angle to the skin surface. The upper bulge closest to the skin surface eventually forms the sebaceous gland, while the lower bulge forms the location of the presumptive follicular stem cells and will later anchor the developing arrector pili muscle to the hair follicle. The arrector pili muscle itself develops independently of the hair follicle and is usually first seen in the dermis near the developing sebaceous gland [66]. The arrector pili muscle grows downwards to connect with the bulge region as the follicle pushes deeper into the dermis. Notably, the arrector pili muscle does not develop in hair follicles growing perpendicular to the skin, such as eyelash hair follicles, follicles of the external auditory canal, and those of the nasal orifice. The outer cells of the bulge, destined to become the sebaceous gland, proliferate and some differentiate into lipogenic cells that progressively accumulate lipid. Maternal hormones cause sebaceous gland hypertrophy and temporarily increase the synthesis and secretion of sebum during the second and third trimesters. With release under the influence of maternal hormones at birth, the sebaceous glands become relatively quies-

Biology of the Hair Follicle

cent until endogenous hormone production increases in puberty. In humans, some hair follicles will develop a third superficial bulge of cells above the cells destined to become the sebaceous gland. The development of this third bulge of cells indicates the formation of an apocrine gland [30]. In humans the face and scalp are the most common locations for hair-follicle-associated apocrine gland development. While hair-follicle-associated formation of apocrine glands can be common in other mammalian species, in humans the association is relatively infrequent. In the second trimester, the hair follicles differentiate to eventually form the seven layers of cells in concentric cylinders seen in mature hair follicles. Beginning near the bulb at the end of stage 4 or at the beginning of stage 5, a core of epithelial cells separates from the peripheral epithelial cells which later become the outer root sheath, continuous with the non-follicular epithelium. The epithelial cell core, resting on the top of the dermal papilla, further differentiates into the inner root sheath Henle, Huxley, and cuticle layers, and the central core of matrix cells that proliferate and give rise to the hair fiber cuticle, cortex and, later in terminal hairs, the medulla [9, 18]. Stage 6 is defined by the visible development and growth of the hair fiber. As the hair fiber and its inner root sheath elongate, the peripheral epithelial cells move aside to allow the cone of the central core of cells to move upwards away from the bulb. By 19–21 weeks’ gestation, the developing hair follicles reach stage 7, in which the hair canals form. In stage 8 the hair follicles are fully formed and the first hair fibers erupt from the skin. The initial lanugo hair of the first anagen hair growth phase grows until 24–28 weeks of gestation.

1.4

Molecular Mediation of Hair Follicle Morphogenesis

These developmental events of hair follicle morphogenesis are controlled by a complex network of sequential activation and inactivation of autocrine, paracrine, and endocrine signaling pathways. Recent research has identified multiple regulatory factors and the essential nature of their influence on hair follicle development, but these molecular controls are not well understood [47]. How these regulators interact with each other, their relative significance, the degree of redundancy in the signaling system, and how these signals determine the development of such a complex structure, its size, and subsequent growth cycle characteristics are still largely unknown. The source of the initial signal for hair follicle development remains unproven. Currently, evidence suggests the first signal emanates from the embryonic meso-

Chapter 1

derm, but whether the epithelium plays a purely passive role in the induction of the first signal is not known. The earliest known molecular pathway activated during hair follicle development involves β-catenin, an intracellular mediator of gene expression. Research has shown that β-catenin is essential for keratinocyte stem cell fate decision [89]. Over-expression of stabilized β-catenin in the epidermis of transgenic mice has been shown to induce de-novo hair follicle morphogenesis, demonstrating its fundamental importance in hair follicle development [24]. In contrast, a lack of functional β-catenin results in keratinocyte differentiation to an epidermal role and a failure of hair follicle development. Products of the WNT gene family are secreted glycoproteins that regulate cell proliferation, migration, and specification of cell fate in the embryo and adult [27]. WNT proteins are classified in part according to their ability to promote stabilization and prevent degradation of β-catenin in the cell cytoplasm. The β-catenindependent WNT pathway signals through cytoplasmic stabilization and accumulation of β-catenin. As it accumulates, it translocates to the cell nucleus where it forms complexes with members of the lymphoid enhancerbinding factor/T cell factor (LEF/TCF) family of DNAbinding factors to activate gene transcription. In mice, activation of WNT signaling is required in the skin for the successful induction of hair follicle development [69]. At this stage in our understanding of hair follicle embryogenesis, WNT-gene-coded proteins are the first extracellular mediators known to be involved in hair follicle development. However, it is possible that there is an even earlier gene-coded signaling mechanism that activates hair follicle development and promotes WNT gene signaling. With the initiation of the first signaling and placode formation, a plethora of extracellular and intracellular mediators is expressed. WNT signals transduced by β-catenin and LEF-1 can elicit the expression of ectodysplasin A (EDA). Experimentally, expression of EDA, activation of its receptor (EDAR), or subsequent downstream activation of the NF-κB pathway mediated by EDAR will each lead to hair follicle development [15]. Not surprisingly, expression of LEF-1 will also induce hair follicle formation as will expression of Noggin, transforming growth factor β2 (TGFβ2), TGFβR-II, β1 integrin and neural cell adhesion molecule (NCAM). Fibroblast growth factors FGF1, FGF2, FGF4, and receptor FGFr2 may also have a hair follicle inductive role, based on studies with chick embryos and the promotion of feather formation. In contrast, multiple inhibitors of hair follicle placode formation, including BMP-2, BMP-4, p75NTR and activin βa, are also expressed in embryonic skin. To add to the already crowded signaling schema, genes encoding several secreted molecules capable of inhibiting the inhibitors of hair follicle in-

3

4

1

A. Vogt, K. J. McElwee, U. Blume-Peytavi

duction, including Follistatin, and Gremlin, are also expressed in developing follicles. The apparently very complex interplay between activators and inhibitors of hair follicle formation, and the respective regulators of activator and inhibitor product expression likely determine the distribution of follicles in the skin [81]. With the development of hair follicles underway, yet more factors are required to regulate the hair germ in its growth and differentiation. Platelet-derived growth factor A (PDGFA) and Sonic hedgehog (Shh) are secreted by the ectodermal cells of the developing hair follicle. They are required for the condensation of the presump-

 

tive dermal papilla cells and for progression of the follicle placode to the peg/bulge hair stages. Asymmetric expression of Shh also polarizes the hair, ensuring outgrowth of the hair follicle in a defined direction. While activin βa can act as a placode inhibitor, activin βa in combination with Shh, hepatocyte growth factor (HGF) and its receptor (MET), transcription factor SOX18, and TGFα have been identified as driving factors during organogenesis. These and other products impel the downgrowth of the hair germ into the dermis. In stages 5–8 of hair follicle morphogenesis, the follicle differentiates into the complex structures that make up a mature hair

Fig. 1.2  Anatomy of the pilosebaceous unit. All hair follicles follow a common architecture. Together with the sebaceous gland (SG) and the arrector pili muscle (M), the hair follicle is part of the so-called pilosebaceous unit. The fibrous sheath (FS) and the epithelial outer and inner root sheaths (ORS, IRS) form concentric layers, which ensheath the hair shaft (HS). Hair growth results from the proliferative activity of matrix keratinocytes in the bulb, which sit on the dermal papilla (DP). The dermal papilla is a condensate of specialized mesenchymal cells with important inductive properties. It also provides nutrition via a capillary loop (C), which is especially prominent in terminal hair follicles. The permanent, superficial component has to be differentiated from the transient cycling component of the hair follicle, which includes the bulb. The morphological dividing line between these two components lies below the bulge (B) region and the insertion of the arrector pili muscle (M). The size and shape of the hair follicles, however, vary with body location and potential functions. In anagen phase, for example, vellus hair follicles from the retroauricular region (left) are approximately six times shorter than scalp hair terminal follicles (right). Each hair follicle has characteristic features. Vellus hair shafts, in contrast to terminal hair shafts, are usually devoid of a medulla (MD). Skirt-like epithelial structures (*), however, can only be found in vellus hair follicles

Biology of the Hair Follicle

follicle. Yet more signaling pathways and product expression are involved in this process, including Notch1, keratinocyte growth factor (KGF), nude, bone morphogenic protein 2 (BMP2), BMP4, MOVO1, multiple HOX genes and, again, mediators such as WNT gene products and their transcriptional activators such as LEF-1. The precise interactions between all these signaling events, however, remain to be unraveled [81].

1.5

Anatomy of the Mature Pilosebaceous Unit

The hair follicle is a complex mini-organ of its own. Each hair follicle is formed by multiple mesenchymal

Fig. 1.3  Histomorphology of a human anagen-stage terminal hair follicle. The hair follicle itself is a complex mini-organ formed by multiple concentric mesenchymal and epithelial cell layers. The fibrous sheath (Fs) ensheathes the outer root sheath (ORS) with an outer (o), middle (m), and inner (i) region and the inner root sheath (IRS), which is further subdivided into Henle layer (He), Huxley layer (Hu), and cuticle (Cu). Matrix cells (Mx) in the hair bulb overly the dermal papilla (DP) and give rise to the hair shaft (HS), which consists of the cuticle (Cu),

Chapter 1

and epithelial cell layers, in total comprising more than 20 different cell populations. Together with the sebaceous gland and the arrector pili muscle, the hair follicle is part of the so-called pilosebaceous unit. The proportions of these components vary among the different hair follicle types (Fig. 1.2). The general hair follicle structure can be divided into regions based on morphology, on whether the structure derives from the ectoderm or mesoderm, and on hair cycling characteristics. At its most basic, divisions can be made between the permanent, superficial structure and the transient cycling component of the hair follicle, which includes the hair bulb (Fig.  1.3). The morphological dividing line between these two components lies just below the bulge region and insertion of the arrector pili muscle [48]. The permanent portion of the hair fol-

the cortex (Co) and, only in terminal hair follicles, the medulla (Me). Melanocytes in the bulb transfer pigment (P) to the hair-forming keratinocytes. The bulge region (B) represents a specialized compartment of the outer root sheath close to the insertion site of the arrector pili muscle, which forms a niche for epithelial and neuroectodermal stem cells as well as various immature cell populations including immature Langerhans cells and mast cells

5

6

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A. Vogt, K. J. McElwee, U. Blume-Peytavi

licle structure can be further subdivided. From the skin surface to the point of the sebaceous gland duct opening to the hair canal it is called the infundibulum. The superficial part of the hair follicle infundibulum, the acro-infundibulum, is lined by intact epidermis including a well developed stratum corneum and a stratum granulosum. Continuous loss of epidermal differentiation occurs towards the isthmus of the lower part of the infundibulum, the infrainfundibulum. The part between the sebaceous gland duct opening and the bulge is called the isthmus. The isthmus is a border zone relatively devoid of distinctive features though notably the thick vitreous membrane between ectoderm and mesoderm visible elsewhere in anagenstage hair follicles becomes much thinner here. The hair follicle isthmus wall consists of two or three rows of flattened cells, whose angle of orientation can be observed to change along the length of the isthmus as the outer root sheath merges with the skin epithelium. The bulge region below the isthmus, which provides the insertion site of the arrector pili muscle, also harbors the so-called bulge region, a specialized compartment of the outer root sheath which forms a niche for epithelial and neuroectodermal stem cells as well as various immature cell populations including immature Langerhans cells and mast cells (see Sect. 1.10.1). The permanent portion of the hair follicle, the part that extends from the skin surface down to lower end of the bulge region, does not undergo significant cyclic changes. However, the presence of hair follicles, their size, and their density effectively lead to a considerable enlargement of the skin surface, which is of particular interest with regard to percuta­ neous penetration processes. The inferior unit, which extends from the bulge to the base of the hair follicle bulb, can be further subdivided into the bulb and suprabulbar region. The epithelial compartments of the hair follicle include the outer root sheath and the inner root sheath, both composed of different cell sublayers, and the matrix cells (see Chap.  7). The outer root sheath extends from the matrix cells in the hair bulb up to the entry level of the sebaceous duct. Outer root sheath cells contain clear vacuolated cytoplasm filled with large amounts of glycogen. Below the isthmus, the outer root sheath is not keratinized. However, at the level of the isthmus, where the inner root sheath disintegrates, the outer root sheath keratinizes without forming granules. Outer root sheath cells express a large diversity of mediators, hormones, and receptors. The inner root sheath consists of three layers, the Henle, Huxley, and cuticle, all of which keratinize. It hardens before the presumptive hair fiber does and is, hence, thought to control the cross-sectional and longitudinal shape of the hair produced (Fig. 1.4). The mesenchymal sheath is separated from the epithe-

 

lial root sheaths by a vitreous or basal membrane. This whole complex is surrounded by a dense vascular network. Free nerve endings form a cuff and provide the basis for intensive piloneural interactions [49]. Hair growth results from the proliferative activity of matrix keratinocytes, which give rise to the hair shaft and the inner root sheath. They are localized in the bulb where they sit on the dermal papilla, the condensate of specialized mesenchymal cells with important inductive properties. In fact, surgical removal of the dermal papilla and the lower dermal sheath prevents hair growth, which indicates the importance of these specialized mesenchymal cells as the key signaling center in hair follicles. Nutrition of the papilla and the overlying matrix cells is provided via a capillary loop located within the dermal papilla of terminal hair follicles. Vellus hair follicle dermal papillae typically do not contain capillaries.

1.6

Hair Fiber Properties

The hair fiber, the most visible product of the hair follicle, is formed of keratin proteins, which are organized as a two-phase intracellular composite consisting of the keratin fibers embedded in an amorphous matrix. Recent genome analyses have increased the number of identified human keratins to 54, grouped into acidic type I and basic-to-neutral type II intermediate filaments (11 of the 28 type I keratins and 6 of the 26 type II keratins are hair keratins). The complex expression patterns of type I and type II hair keratins in the hair follicles as well as hair-specific expression of epithelial keratins are summarized in Table 1.1 [77]. To accommodate the growing number of keratin genes, a new consensus nomenclature for mammalian keratins was recently proposed, which also allows the incorporation of keratins from other mammalian species [76]. The matrix proteins, also referred to as keratin-associated proteins, are a major component of the hair fiber and play a crucial role in forming a strong hair shaft through a cross-linked network with keratin intermediate filaments. Generally, division occurs into high-sulfur proteins, ultra-high sulfur proteins and high-glycine-tyrosine proteins, which are differentially expressed in the cortex, cuticle, and matrix [58]. In terms of raw elements, on average, hair is composed of 50% carbon, 20% oxygen, 17% nitrogen, 6% hydrogen, and 5% sulfur. Hair also contains trace amounts of magnesium, arsenic, iron, chromium, and other metals and minerals. The visible hair shaft of terminal hair follicles consists of three layers: cortex, cuticle, and medulla. The central medulla contains polygonal cells with a sponge-

Biology of the Hair Follicle

Fig.  1.4a–f  Cytokeratin expression pattern in human vellus and terminal hair follicles. The expression of differentiation markers such as cytokeratins is closely related to the anatomical layers of the hair follicle. Except for some hair-follicle typespecific characteristics, such as the skirt-like epithelial structure of vellus hair follicles (*), all hair follicles follow the same architecture. This is illustrated in this figure which, in each pan-

Chapter 1

el (a–f) displays one vellus hair follicles (left) and one terminal or intermediate hair follicle (right), respectively. The inner root sheath displays immunoreactivity against cytokeratin 13 (a) and trichohyalin (b), while immunoreactivity against cytokeratin 18 can predominantly be found in the Huxley layer (c). Anticytokeratin 7 specifically stains the cuticle (d). Cytokeratin 17 (e) and cytokeratin 19 (f) are markers of the outer root sheath

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Table 1.1  Human hair keratins and hair-follicle-specific epithelial keratins with their expression sitesa [77]

1

Type I

Expression site

Type II

Expression site

Hair keratins (hair fiber keratins) K31 [Ha1]

Entire cortex

K81 [Hb1]

Mid cortex

K32 [Ha2]

Cuticle

K82 [Hb2]

Cuticle

K33a [Ha3-I]

Mid cortex

K83 [Hb3]

Mid cortex

K33b [Ha3-II]

Mid cortex

K84 [Hb4]

Absent from the hair follicle present in tongue

K34 [Ha4]

Upper cortex

K85 [Hb5]

Matrix, precortex cuticle

K35 [Ha5]

Matrix/precortex, cuticle

K86 [Hb6]

Mid-cortex

K36 [Ha6]

Mid cortex

K37 [Ha7]

Central cortex vellus hairs; medulla sexual hairs

K38 [Ha8]

Single cortex cells

K39 [Ka35]

Upper cuticle

K40 [Ka36]

Cortex, medulla, upper cuticle

Hair-follicle-specific epithelial keratins

a

K25 [K25irs1]

IRS (Henle, Huxley, cuticle), medulla

K71 [K6irs1]

IRS (Henle. Huxley, cuticle), medulla

K26 [K25irs2]

IRS (Upper cuticle)

K72 [K6irs2]

IRS (cuticle)

K27 [K25irs3]

IRS (Henle, Huxley, cuticle), medulla

K73 [K6irs3]

IRS (cuticle)

K28 [K25irs4]

IRS (Henle, Huxley, cuticle), medulla

K74 [K6irs4]

IRS (Huxley)

K75 [K6hf ]

Companion layer, medulla

The keratin designations follow the new keratin nomenclature [76] with their former names in brackets.

like appearance. In terminal hair produced in childhood the medulla may be absent or fragmented. In fine vellus hair fiber the medulla is always absent. Around the medulla, the cortex forms a layer of cornified fibrous cells with a longitudinal orientation. When fully developed, these cells are packed with keratin filaments. The hair fiber cortex contains melanosomes, which determine the color of the hair fiber. Homogenous oval eumelanin granules and lamellar pheomelanin granules, in variable composition and density, form the wide spectrum of dark to fair hair. The outermost layer of the hair fiber, the cuticle, consists of multiple layers of corneocytes. It is thin and translucent allowing light to penetrate to the cortex pigments. There are a wide range of biometric measurements of hair, such as the diameter and structure of the hair

shaft, most of which are genetically programmed (see Chap.  24). Terminal hair diameter and cross-sectional shape are key differentiating features, which can be approximated by hair color and ethnicity. While Caucasians typically have terminal scalp hair with a cross-sectional diameter ranging from as low as 40 µm in blonde-haired people to 90 µm in dark-haired individuals, average hair fiber diameters are higher overall in African and Asian populations (Table 1.2). Hair cross-sectional shape also varies with ethnicity. While Caucasians typically grow hair with an elliptical cross-sectional shape consistent with straight or wavy hair, Asian hair is typically circular in cross-section consistent with straight hair [72]. In contrast, African populations have a very elliptical or even ribbon-like cross-sectional shape to their terminal hair fiber. The ribbon-like shape makes hair relatively

Biology of the Hair Follicle Table 1.2  Terminal hair diameter [16, 17, 72] Type

Diameter – typical range (µm)

Blonde-haired Caucasian

40–80

Dark-brown/black-haired Caucasian

50–90

Red-haired Caucasian

50–90

African (African-American)

60–100

Asian (far East)

80–120

inflexible across the long cross-sectional axis but very flexible across the short axis consistent with curly hair. The shape of the hair shaft is partly formed by the shape of the hair follicle. Major determinants of the overall individual appearance of the hair fibers are the position of the hair bulb relative to the rest of the hair follicle, the size and shape of the dermal papilla, and the curvature of the hair follicle along its length. These parameters determine the diameter and cross-sectional shape of the hair shaft and the number of twists and windings (curl) per unit length of each individual hair. While in large part these properties are defined by the hair follicle that produces the hair fiber, environmental factors from chemical exposure to friction may also modify the nature of the hair fiber. Hair fibers are enormously durable material with the potential to survive thousands of years, as seen with Egyptian mummies for example. Hair is also very strong: the cross-sectional area of hair fiber and the structural integrity of the cortex determine its overall strength. Healthy hair fiber has a tensile strength around 180–190 MPa [90], which makes hair about as strong as copper wire of the same diameter. Hair fiber also has elastic properties: extension of 10% of its original length under tensile stress is possible without damage. Extension of 35%–50% is possible, but results in permanent damage of the inner fiber structure. Hair shaft abnormalities that may reduce hair strength and quality are due to genetic changes in the shape, diameter, and structural composition, to surface cuticle defects, or are due to environmental manipulation such as physical or chemical damage to the cuticle and cortex. In curly hair, the cuticle of the outer curl is relatively thin and more fragile and consequently is sensitive to exogenous stress such as heat or chemicals. Disruption and loss of the hair cuticle, whether through genetic defects or acquired from the environment, significantly weakens the overall strength of the hair and may result in splitting and breakage. More limited changes in the structure of

Chapter 1

9

the cuticle can lead to impaired water retention in the underlying cortex with loss of humidity. For a healthy appearance, hair fibers ideally need to retain approximately 17% humidity. In fact, water retention up to 35% is possible. Hair length also varies up to 2% depending on the air humidity [45, 90].

1.7

Hair Follicle Types

Hair and hair follicles occur diversely all over the human body except on palms of the hands, soles of the feet, glabrous foreskin, and lip vermillion. Based on the structure and shape of the hair fiber, gross size, and time of appearance on the body, several hair follicle types can be differentiated (Table 1.3). Generally, lanugo hair-producing hair follicles, vellus hair follicles, intermediate hair follicles and terminal-hair-producing follicles can be identified [71]. A hair follicle may move from one category to another as it changes size and hair fiber production over time.

1.7.1

Lanugo Hair

Lanugo hair is fine, soft, poorly pigmented and has no central medulla. Produced in utero, it is the first hair growth produced by developing hair follicles. Lanugo hair may also be observed in adults with various forms of hypertrichoses [82].

1.7.2

Vellus Hair

Vellus hair is non-medullated, fine, and poorly pigmented. Vellus hair continues to grow throughout life. Even in areas usually considered to have only terminal hairs, such as the scalp, vellus hair may constitute 7%–25% of the hair present.

Table 1.3  Typical hair characteristics Hair type

Characteristics

Lanugo

2 mm length

Vellus

60 µm diameter; >2 mm length

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1.7.3

Intermediate Hair

Intermediate hair is first observed postnatally as the scalp hair growth subsequent to the initial lanugo hair growth. Intermediate hair is characterized by a relatively rough cuticle, sparse pigmentation and a fragmented or absent medulla.

1.7.4

Terminal Hair

Terminal hair has a larger cross-section diameter as compared to other hair fiber types. It is pigmented, with the exception of those hairs affected by canities, and grows for a significant length. The size and shape of terminal hair varies with body location and potential function. Terminal scalp hair serves a key role as protection from UV light and as an insulator against heat and cold. Specialized terminal hair such as eyebrows and eyelashes may protect the eyes by draining or sweeping away fluids and dust [50]. Eyelashes have the largest diameter of all body hair, strong pigmentation, and they have a relatively short active growth phase. Nasal hair may play a role in preventing insects and other airborne material from entering the nasal cavity (Table 1.4). This classification of hair follicles, based on the nature of the hair fiber produced, can be further refined by the morphological characteristics of the hair follicles themselves. The primary anatomical distinction of human hair follicles depends largely on gross size to differentiate those producing vellus hair from those producing terminal hair. Vellus hair follicles are small and penetrate the reticular dermis but not the subcutaneous fat layer. As a morphological characteristic, vellus hair follicles frequently display skirt-like epithelial structures or perifollicular connective tissue capsules, with

 

a striking clear space between the outer root sheath and these skirt-like structures, or between the outer root sheath and the perifollicular connective tissue capsule. This space is filled with mucinous substance that is rich in perifollicular nerve endings and, among other cell types, contains elongated fibroblasts and mast cells [56]. The typical dermal papilla in a vellus hair follicle contains just 10–30 cells. Compared to vellus hair follicles, a typical terminal scalp hair follicle dermal papilla contains 200–400 cells and correspondingly the rest of a terminal hair follicle is much larger. Terminal hair follicles reach into the deep dermis and their bulbs are located in the subcutaneous fat. Further subclassification can be made based on the morphology of hair follicles. For example, sebaceous hair follicles in seborrheic regions of the skin display rela­tively large well-developed sebaceous glands associated with small, fragile hair follicles. Hair follicle types may also be differentiated by their functional characteristics, such as the different responsiveness to androgens of terminal hair follicles in the scalp as compared to those in the beard, the axilla, and the pubic region. While all hair follicles have the same basic developmental and structural characteristics, there is significant variation in morphological presentation. However, of the hair follicles located in the different body regions, hair follicles of one predominating subtype form rather homogenous groups with only moderate intra- and inter-individual variability.

1.8

Hair Cycling

Traditionally, three phases of the growth cycle are recognized: a growth phase (anagen phase I–VI), a regression phase (catagen), and a resting phase (telogen). For

Table 1.4  Types of terminal hair in humans [23] Hair type

Length – typical range (mm)

Description

Scalp

100–1000

Medullated with tapered tip in uncut hair

Eyebrow and eyelash

5–10

Medullated and curved with punctuate tip

Beard and moustache

50–300

Complex medullary processes, more irregular in structure, blunt tip

Body

5–60

Irregularly medullated, fine tip

Pubic

10–60

Coarse, kinked, irregular and asymmetrical cross-section

Axillary

10–50

Coarse, less kinked than pubic hair, blunt tip, often abraded due to friction

Biology of the Hair Follicle

Chapter 1

Fig. 1.5  Hair cycle. During one hair cycle a complete remodeling of the non-permanent portion of the hair follicle occurs, which is controlled by finely tuned changes in the local signaling milieu. Traditionally, three phases of hair growth are recognized: a growth phase (anagen I-III), regression phase (catagen), and resting phase (telogen). Recent research suggests that shedding of the hair fiber is an active process, which has led to

the introduction of the term “exogen” to describe this event. As another novel phenomenon in hair cycling, empty hair follicles after shedding of the hair fiber were reported. This interval of the hair cycle, in which the hair follicle remains empty after the telogen hair has been extruded and before a new anagen hair emerges, has been named “kenogen”

identifying and classifying each of the individual stages of hair follicle cycling (Fig.  1.5) refer to [53]. These cyclic transformations are controlled by finely tuned changes in the local signaling milieu, based on changes in the expression of cytokines, hormones, neurotransmitters and their receptors as well as transcription factors and enzymes, which act via endocrine, paracrine or autocrine routes. In fact, hair cycling parallels morphogenesis involving multiple signaling events incorporating developmental pathways such as reoccur during the different hair cycle stages. The hair cycle includes a complex remodeling and regeneration of the complete non-permanent portion of the hair follicle. It is not just the hair follicle epithelium, but also the mesenchyme, the extracellular matrix, the vasculature and innervation, and the hair-follicle-associated cell populations that undergo dramatic changes. In fact, in species with synchronized hair follicle cycling, the architecture and

physiology of the entire skin, including its immune and gene expression status, undergo substantial changes subsequent to prior switches of multiple hair follicles from one stage of their cycling activity to another.

1.8.1

Anagen

During the anagen phase, the hair is actively growing and materials are deposited in the hair shaft by cells found in the follicle. Metabolically active and dividing cells above and around the dermal papilla of the follicle grow upward during this phase to form the hair shaft. The anagen phase includes not only the growth of the hair, but also a highly increased proliferative rate of all hair follicle cells in all epithelial compartments, with the highest activity observed in matrix cells. Anagen duration is genetically predetermined and varies with the

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size and body location of the hair follicle. An anagen growth phase may last several years, as seen in terminal hair follicles on the scalp, but anagen may persist for just a few weeks in terminal hair follicles on the extremities (for associated melanin production and hair shaft pigmentation see Chap. 4).

1.8.2

Catagen

The anagen phase is followed by a short resting phase, catagen, which can be divided into eight subphases starting with late anagen and ending in early telogen. The regression of the hair follicle in catagen is characterized by a cessation of protein and pigment production, involution of the hair follicle, and a fundamental restructuring of the extracellular matrix. Massive apoptosis in the infrabulbar, transient, portion of the hair follicle leads to regression of the hair follicle and the formation of a fibrous streamer. Because the onset of these apoptotic events seems to be predetermined and finely orchestrated, programmed cell death is probably the more accurate term to describe these events. When the part of the hair follicle in contact with the lower portion of the hair becomes attached to the hair shaft, the so-called club hair is formed. Catagen is the first component of the initial hair cycle occurring after morphogenesis.

1.8.3

Telogen

In telogen, the hair follicle has regressed to about half of its previous size and does not extend beyond the upper dermis. Morphologically, a “finger” of epithelial cells overlies a cluster of dermal fibroblasts; the remains of the dermal papilla. The dermal papilla is no longer enveloped by surrounding epithelial cells and sits as a small ball of cells in close association with the epithelial cell finger. The epithelial cells of the lower telogen follicle do not show significant DNA or RNA synthesis, nor is there any synthesis of proteins characteristic of the anagen follicle, such as trichohyalin and the hair cortical keratins. Notably however, keratin 14 (K14) synthesis does continue in the epithelial sac to which the telogen hair fiber anchors. In telogen follicles the volume of the dermal papilla extracellular matrix is much reduced, and dermal papilla cells have scant cytoplasm and are relatively quiescent. The telogen hair shaft, the club hair, can be retained for months in this epithelial sac.

1.8.4

Exogen

Recent research suggests that shedding of the hair fiber is a highly controlled, active process, which differs

 

from the quiescence normally found during the telogen phase. Consequently, the term “exogen” has been introduced to describe this event as a specific process of its own during hair follicle cycling [80]. In fact, more detailed studies on this process suggest that the former concept, based on the assumption that the newly formed hair fiber pushes the resting shaft outward to effect shedding, is unlikely. When a shed hair shaft root is compared to a plucked telogen hair shaft root by light or electron microscopy, major morphological differences are apparent. The telogen root is made of packed nucleated cells which show intracytoplasmic fractures surrounding a cornified core making up the shaft. The exogen root, in contrast, is made of very few cells and these cells are separated at their outer edge by intercellular cleavage. The morphology of the hair root suggests that the exogen process involves a proteolytic event that occurs between the moving cells of the telogen shaft base. The nature of this shedding process remains to be identified. A possible role of desmoglein and proteolytic events was suggested [37].

1.8.5

Kenogen

As a novel phenomenon in hair cycling, empty hair follicles after shedding of the hair fiber were reported when using phototrichograms and the term “kenogen” was suggested to describe this interval of the hair cycle in which the hair follicle remains empty after the telogen hair has been extruded and before a new anagen hair emerges. Kenogen can be reproducibly observed in healthy skin; however, frequency and duration have been reported to be greater in men and women with androgenetic alopecia [68].

1.8.6

Duration of the Hair Cycle

The duration of the different phases depends on the type and localization of the hair follicle. Under physiological conditions, 85% of the scalp hair is in anagen and approximately 15% is in the telogen phase [71, 87]. The anagen phase of scalp hair follicles typically persists for 2–6 years, although a few individuals may have anagen growth phases of much longer duration. The duration of anagen is a major determinant of the maximal hair length. The anagen phase of hair follicles of the eyebrows, in contrast to scalp hair follicles, is only 70 days, while eyelashes grow for 100–150 days. The duration of telogen in hair follicles is also an important considera­ tion when understanding the consequences of changes in the hair growth cycle. The body hair follicles are characterized by an increased telogen frequency and duration as compared to scalp hair follicles (Table 1.5). Un-

Biology of the Hair Follicle Table 1.5  Hair cycle duration with body location [14, 35, 36, 62, 85] Location

Hair growth state

Typical time duration

Scalp

Anagen

2–6 years

Catagen

2–3 weeks

Telogen

3 months

Anagen

4–14 weeks

Telogen

10–18 weeks

Anagen

6–12 weeks

Telogen

7–13 weeks

Anagen

19–26 weeks

Telogen

13–34 weeks

Beard

Arms

Legs

der physiological conditions, each hair follicle continues to cycle throughout life.

1.8.7

Hair Growth and Cycle Regulation Potential of the Dermal Papilla

The potent inductive ability of dermal papilla cells to promote hair follicle formation has long been recognized. The size and secretory power of the dermal papilla determine the size of the anagen bulb, and subsequently the diameter of the hair shaft produced by the hair bulb, and the rate of hair growth, respectively [20]. The dermal papilla also dictates the duration of anagen and thus, in combination with the rate of hair growth, the potential maximum length that hair fiber can reach. What determines the duration of anagen within dermal papilla cells is not clear, but several hypotheses have been suggested involving variations on a biochemical clock mechanism [59]. Different concepts, which are still being controversially discussed, include the idea of accumulation of an endogenous inhibitor during anagen, which, at a threshold level, inhibits mitosis thereby causing transition to catagen phase. Dictation of hair cycling length by the (limited) number of mitoses of slow-cycling epithelial cells in response to mesenchymal signals is being discussed, as is the presence of as yet unidentified endogenous oscillating signals or embryonic pathmakers. Whilst it is unlikely that the epithelial component is entirely passive in determining the size and shape of hair follicles, numerous studies have confirmed that the mesenchymal signaling component predominates. Many investigators have found that follicular dermal papilla cells dissected from the base of an anagen hair

Chapter 1

follicle, either fresh or after tissue culture expansion, can induce new hair follicle formation in rodents if placed in proximity to non-follicular epithelium [34]. This process has been variously called the follicular neogenesis model, hair follicle replication, and hair multiplication. In addition, labeled cultured dermal papilla cells and cells from the bulbar connective tissue sheath of rodent vibrissae have been shown to be incorporated into resident pelage hair follicles making them larger and prolonging the duration of anagen, suggesting that the introduced cells can override the inherent properties of resident dermal papilla cells [43]. This process has been called the morphogenetic switch model, follicular amplification, or, in the case of damaged follicles, follicular reactivation. Thus far only one published study has indicated that follicular replication is possible in humans. Reynolds et al. transplanted microdissected connective tissue sheath from the scalp of a man to the forearm of a woman. After 3–5 weeks, new follicles were observed at the site of transplantation with the mesenchymal portion arising from the transplanted donor cells [70]. These and other studies demonstrate that dermal papilla cells retain knowledge of the size and shape of the hair follicle they should form and they retain a memory of their hair cycle clock.

1.8.8

Developmental Pathways, Cytokines, Growth Factors, and Neuroendocrine Factors

Especially in the anagen phase, parallels are seen in the development of the newly formed hair follicles compared to the events observed during morphogenesis. In fact, part of morphogenesis is recapitulated in each hair cycle, involving the expression of morphogens and mediators concerned with pattern formation, including the Hedgehog and Wingless family. Shh and its downstream targets, which drive proliferation during folliculogenesis, also promote cell proliferation in anagen hair follicles. Wnt signaling determines the differentiation of epithelial stem cells into hair follicle keratinocytes. Ablation of Wnt signaling blocks initiation of a new hair cycle. Moreover, activation of the Wnt pathway has been reported to be necessary to maintain the cultured papilla cells’ ability to induce hair follicles. Epimorphin, a mesenchymal morphogen that has been shown to mediate epithelial–mesenchymal signaling interactions in various organs, is involved in telogen-to-anagen transition. Differential gene expression analyses in the skin recently identified genes encoding hair-specific keratins and keratin-associated proteins (KAPs) as major groups of presumptive downstream effectors of the homeobox gene Hoxc 13. The natural hair cycle, however, involves many more signaling events and pathways (including

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cytokines, growth factors, adhesion molecules, neuroendocrine mediators, and hormones), and the equipment of each cell with specific subsets and combinations of receptors and enzymes regulates the responses to these numerous, frequently redundant, stimuli [2]. Although sensitive to changes in the systemic blood levels of hormones, the fine-tuning of synthesis, receptor expression and receptor binding, and enzyme activity in and around the hair follicle are major determinants of normal hair cycling This is especially so since the hair follicle has been shown to produce complete hormone cascades on its own, which act on the different cell populations in endocrine, paracrine, and autocrine ways. For example, the production and expression of signals and receptor components of the gonadotrophinreleasing hormone (GnRH), corticotrophin-releasing hormone (CRH), and pro-opiomelanocortin (POMC) systems have been characterized in detail leading to the term “brain–hair follicle axis” with suggested equivalence to the hypothalamo–hypophyseal axis in the brain (see Chap. 3). The differential expression of receptors and enzymes also provides the basis for the variable responsiveness to sexual hormones and their metabolites in the different hair follicle types. Androgens have diverse effects on hair follicles in different body regions. Androgenrelated effects vary from essentially non-existent (e.g., on eyelashes), to weak (on temporal and suboccipital region hair), to moderate (on extremity hair), to strong (on facial, parietal region, pubic, chest, and axillary hair). Differential effects are also observed in scalp hair; occipital terminal hair follicles, for example, are largely independent of androgen action, while androgen-dependent beard hair in males forms only under adequate androgen stimulus. Also, in males, hair loss in androgenetic alopecia is most pronounced in the tempoparietal regions above the temples and on the vertex. Androgen sensitivity of the individual hair follicles also remains after transplantation of pilosebaceous units; a feature called “donor dominance” (see Chap. 22).

1.9

Hair Growth Changes with Age

The first hair to be produced by the fetal hair follicles is lanugo hair, which is usually shed between the 32nd and 36th weeks of gestation. In up to one-third of babies, however, lanugo hair growth, to some extent, is retained until birth. The presence of lanugo hair over the entire body at delivery can be a sign of prematurity. During the fetal period, all scalp hair follicles are in the same hair cycle phase. Within a few weeks after birth, regression of the hair follicles to catagen occurs

 

in two waves starting at the frontal zone, which then migrates over the scalp from the forehead to the nape of the neck. There is an area over the occiput in which the primary hairs do not enter telogen until after birth. These hairs remain in the scalp for 8–12 weeks and then fall. As telogen hairs predominate on the occiput, their fall commonly produces an area of temporary, localized alopecia. In the subsequent hair cycle, intermediate hair fibers form the first scalp hair and an asynchronous hair cycle is established following a mosaic pattern. There is considerable variation in the age at which the mosaic pattern is fully developed. Frequently, children have only sparse hair growth in their initial months of life until the first postnatal telogen phase. Subsequent hair growth is much stronger and more consistent in density. On the scalp, the fully developed terminal hair follicle is detectable around 12–16 months of age. After the loss of the fine lanugo hair, vellus hair follicles cover most of our body surface and, hence, are the most prominent hair follicle type in the postnatal period. Initially, only the hair of the eyebrows, eyelashes, and scalp develops into terminal hair and becomes highly pigmented. Over time, depending on the age of the individual, gender, and body region, vellus hair follicles can transform and begin to produce terminal hair fiber. At puberty, the vellus hair in some body areas is replaced by longer, coarser, pigmented terminal hair. Growth first starts in the pubic region; then the eyelashes and eyebrows become thicker as compared to prepuberty. Axillary hair and male facial hair begin to appear about 2 years after the growth of pubic hair begins. Body and beard hair continues to grow long after puberty, stimulated by male hormones that, paradoxically, also cause regression of scalp terminal hair follicles into vellus hair-like follicles in androgenetic alopecia. The likelihood of the presence of androgen-induced terminal hair growth on body regions varies with age, sex, and ethnicity. In general, Caucasians have a greater frequency of body hair growth as compared to Asian and African peoples. While beard hair growth is almost always present in Caucasians, beard growth can be more limited in Asian ethnic groups and extremely limited in aboriginal peoples. Postpuberty hair-growth rates vary with body location (Table 1.6). Prepuberty, hair growth is most rapid on the vertex of the scalp, but postpuberty the hair-growth rate on the vertex slows and becomes less rapid as compared to the hair-growth rate on the occiput in both males and females. The rate of terminal hair growth on the scalp occiput, thigh, and eyebrow remains relatively consistent throughout adult life, but the growth rate of more androgen-responsive hair follicles on the chin and axillary hair changes with advancing age. Hair follicles on the chin in men are the fastest growing hair follicles,

Biology of the Hair Follicle Table 1.6  Rate of terminal hair growth in adults [54, 63, 74] Location

Typical hair growth per day (mm)

Chapter 1

15

Table 1.7  Typical numbers of scalp hair follicles [22, 41] Type

Number

Chin

0.38

Blonde-haired Caucasian

130,000

Scalp

0.35

Dark-brown/black-haired Caucasian

110,000

Axilla

0.30

Red-haired Caucasian

90,000

Thigh

0.20

African (African-American)

90,000

Eyebrow

0.16

Asian (far East)

90,000

Table 1.8  Hair follicle density with age (absence of alopecias) [6, 19, 25, 83] Location

Full-term fetal scalp Adult scalp Full-term fetal forehead

Mean density of hair 2 follicles in skin (/cm ) 1135 615 1060

Adult forehead

765

Full-term fetal thigh

480

Adult thigh

Table 1.9  Estimated number of hair follicles in the skin by body region [83] Location

Number of follicles

Head

1,000,000

Trunk

425,000

Arms

220,000

Legs

370,000

Approximate total

2,000,000

55

producing 0.38 mm of fiber per day in adulthood, but this rate slows somewhat with age [54]. Androgens may also be a factor in the reduction of the hair-growth rate and atrophy of axillary hair follicles in old age. At birth, each human being possesses between two million [83] and five million [21] vellus and terminal hair follicles. Of this total, 100,000–150,000 hair follicles are located on the scalp [21, 50]. The number of scalp hair follicles varies with the individual’s skin, hair color, and ethnicity. Dark-haired individuals tend to have fewer scalp hair follicles than fair-haired individuals (Table 1.7). Overall, scalp hair density is slightly greater in boys than in girls and all individuals have a density gradient of hair follicles from the vertex to the occiput. Hair follicle density on the body changes in different body regions with age (Table 1.8). All hair follicles form during embryonic development and no additional follicles are naturally formed after birth in humans [7]. This is not always true for other mammals as, for example, deer antler velvet involves annual formation of new hair follicles [42]. As compared to an adult, the surface area of skin in newborn humans is relatively small and so the hair follicles are relatively densely packed together. With growth, the same number of hair follicles must be spread over a progressively larger unit area of skin. Different regions of the body grow at different rates and, subse-

quently, hair follicles in some regions are spread further apart than in others. While our heads grow somewhat after birth, the greatest increase in growth occurs in our limbs. Consequently, hair follicle density on the head remains relatively high while density on the lower arms and legs is much reduced in adults (Table 1.9).

1.10

Specialized Hair Follicle Compartments

1.10.1 Stem Cells The cyclic activity of the hair follicle requires the regeneration and new assembly of its non-permanent portion during each new hair cycle. This enormous plasticity is accomplished by the presence of multipotent adult stem cells, which reside in rather undifferentiated, quiescent states and form precursors, transient amplifying cells, which provide further proliferation and differentiation into the different cell types. Such pools of adult stem cells have been identified in various self-regenerating tissues [12]. Label-retaining cell analyses, which followed BrDu or [3H]TdR labeling for periods of up to over 1 year, revealed that the slowest cycling cells within

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the skin reside in a specialized compartment of the hair follicle epithelium termed the bulge region. Here, cell label retention of 14 months was observed in mice and of at least 4 months in humans [13]. The bulge region is a contiguous part of the outer root sheath, which marks the lower end of the permanent portion of hair follicles. On histological sections of human hair follicles, it can be readily identified as a unilateral thickening of the outer root sheath. The quiescent nature of bulge cells was also demonstrated by labeling experiments in mouse models and on human skin grafted to immunodeficient mice, where uptake of the labeling substances [3H]TdR and BrDu was only observed at the onset of the anagen phase [31]. Studies using colony-forming experiments as well as holoclone analyses confirmed a high proliferative potential [52]. While earlier studies suggested that bulge-derived cells also migrate into the interfollicular epidermis, recent investigations using transgenic mouse models demonstrated that such migration only occurs under wound healing conditions, while the homeostatic regeneration of the interfollicular epidermis emanates from the interfollicular epidermis itself [32, 40]. This supports the clinical observations and early studies on animal models suggesting that hair follicles significantly contribute to epidermal repair [4]. To understand why stem cells are preferentially located in a specific niche such as the bulge region, studies on the microenvironment in the bulge are gaining importance. Balanced c-myc expression seems to be crucial, as its overexpression in transgenic mice causes follicle stem cells to proliferate and to terminally differentiate [5]. Microarray profiling has identified over 150 genes, which are preferentially expressed in the bulge region relative to interfollicular epidermis. Purification and enrichment of bulge stem cells, however, remains a challenge, especially since critical differences in gene expression have been found between human and murine bulge cells. Due to their relative quiescence, bulge cells are more susceptible to the accumulation of genetic damage and retention of carcinogens over prolonged periods of time [51] and consequently they may be more likely to form tumors. For example, there is molecular evidence for their involvement in the formation of basal cell carcinomas and trichoepitheliomas [1]. The identification of melanocyte stem cells [57], mesenchymal stem cells [39], mast cell precursors [38], immature Langerhans cells [26], and neural-like stem cells [3] further underlines the enormous plasticity of hair follicle cells and intensive research efforts are ongoing to explore ways to utilize the hair follicle as an autologous source for stem cell recovery for the treatment of a wide variety of diseases.

 

1.10.2 Immunology The hair follicle, as a physiological break in the skin barrier, is a conduit for intensive interactions with the environment. Accordingly, antigen-presenting cells can be found at particularly high densities in hair-folliclebearing skin [84]. They are particularly concentrated around the upper portion of the hair follicles, where they are found not only in the suprabasal layer, but also in the basal layer of the outer root sheath. In contrast, however, very low numbers of immune cells are found in the transitory hair follicle compartments [11]. The restricted distribution of intraepithelial T cells and Langerhans cells, accompanied by suppressed majorhistocompatibility-complex-II- (MHC-II-) dependent antigen presentation, the virtual absence of MHC class I expression, and the concomitant high expression of immunosuppressive mediators such as alpha melanocytestimulating hormone (α-MSH), transforming growth factor β1 (TGFβ1), and adrenocorticotropin (ACTH), suggest that the hair follicle, between the bulb and the lower bulge region, constitutes an area of transient immune privilege. Just like other immunoprivileged tissues, such as the anterior eye chamber, the hair bulb is devoid of lymphatics and is ensheathed by a special extracellular matrix barrier, both of which might hinder immune cell trafficking. The immunoprivileged state occurs in a hair-cycledependent manner. In mouse skin, local production of TGFβ1, ACTH and αMSH is highest when all hair follicles are synchronized in the anagen phase [78]. In fact, human hair follicles are MHC-I-positive during telogen and the late anagen phase [33]. The physiological significance of the immune privilege in the anagen hair growth phase, however, remains poorly understood. It is conceivable that its breakdown plays a role in the pathogenesis of autoimmune diseases affecting the hair follicle such as alopecia areata, lupus erythematosus, scleroderma, graft-versus-host-disease or lichen planopilaris. The inflammatory reaction in alopecia areata targets predominantly the transitory compartments of anagen hair follicles, an observation which gave rise to the concept of immune-privilege collapse in alopecia areata pathogenesis [60]. This hypothesis of functional immunoprotection against autoimmune reactions is supported by recent research by Rosenblum et al. suggesting that CD200, which reportedly inhibits autoimmunity, is an important regulator of the immune-privileged state of the human hair follicle and that skin deficient in CD200 is highly susceptible to hair-follicle-associated inflammation and immune-mediated alopecia [73]. Extensive further studies, however, will be required to unravel all the different facets of the hair follicle immune system

Biology of the Hair Follicle

and their implication in the pathophysiological events observed in inflammatory hair diseases.

1.10.3 Neuroimmunological and Neuroendocrine Interactions The hair follicle is both a target for, and a source of, immunomodulatory stress mediators [61]. The dense perifollicular meshwork of sensory nerve endings is closely associated with mast cells, endothelial cells, and macrophages [64], rendering the hair follicle a potential site for intensive pilo-neural interactions. Neuroendocrine mediators including substance P, cortisol, ACTH, CRH, POMC, and neurotrophins, all of which are expressed in the hair follicle, exert hair-growth-modulating effects. Local regulatory feedback systems similar to the hypothalamic–pituitary–adrenal axis have been identified (see Chap. 3). In particular, vellus hair follicles on the head, upper trunk, and upper extremities are innervated by Merkel nerve endings, i.e., specialized Merkel cells filled with neuroendocrine granules, which occur in association with nerve fibers [86] (see Chap. 5).

1.10.4 Melanocytes Melanocytes, which transfer melanosomes to the surrounding keratinocytes and thereby direct the pigmentation of the hair fiber, lie in the matrix zone. Melanocyte activity is hair cycle dependent. At the end of each hair cycle melanocytes reduce melanin production and retract their dendrites. Therefore, localized canities can often be found as an unpigmented proximal end to a telogen hair fiber, which is unpigmented because melanin production stops at the end of each hair cycle slightly in advance of hair fiber growth termination. In aged grey and white hair, the melanocyte number in the basal hair matrix is reduced, remaining melanocytes display signs of degeneration, and the hair fiber only contains melanin debris [79] (see Chap.  4). Neuroectodermal crest stem cells, which may give rise to immature melanocytes, have been identified in the bulge region.

1.11

Experimental Techniques

Due to the complex structure and regulation of the hair follicle, with more than 20 cell populations and numerous signaling events involved, experimental hair research is a challenging task and the experimental model has to be chosen carefully and appropriately for each

Chapter 1

question to be answered. Being localized at the skin surface, hair growth and hair abnormalities are, on first glance, easy to monitor. Hair fibers and hair roots are easily accessible for non-invasive collection. In clinical diagnostics, traditional trichograms allow evaluation of hair cycling anomalies using simple light microscopy. Phototrichograms, and the recent development of the TrichoScan™ technique allow quantification of hair growth in vivo [29]. In addition, the use of global photography techniques is a popular approach in treatment evaluation. Whilst these approaches are very useful for disease diagnosis and clinical treatment trials, they provide relatively limited information about the hair follicle in the skin. To characterize hair follicles requires more invasive techniques. In the clinic this generally involves tissue biopsy and histological analysis of the hair follicle structure. For the research laboratory, many more experimental techniques have been developed as aids to our understanding of skin appendage formation and growth. There are advantages and limitations to any experimental technique. Conventional analysis methods of sections of cryo-preserved or paraffin-embedded tissue remain invaluable screening tools for the evaluation and validation of expression patterns of RNA or protein, using techniques such as in situ hybridization and immunohistochemistry respectively. Material for gene expression profiling can also be harvested from plucked hair follicles. In fact, RNA of sufficient quantity and quality to use for microarray hybridizations can be obtained from as little as one single hair fiber. However, while these approaches using tissues enable evaluative studies to be performed, they do not permit studies to determine the functional significance of a particular gene or its product in hair growth or disease. For functional studies, one must use living tissue in some fashion. Animal models of hair follicle development and hair diseases have grown in popularity in recent decades. Developmental biology using model organisms such as Drosophila, Xenopus and zebrafish have provided valuable insights into the role of conserved signaling pathways including Hedgehog or Wingless in pattern formation and the formation of skin appendages in general. Mammalian models, especially the development of genetically engineered mice which can be used to study the regulatory events of hair follicle development and hair growth, are directly relevant to hair follicle biology in humans [67]. Rodent models in particular have many advantages that enable research. Their ready availability, rapid breeding, known genetics in inbred strains, the ability to modify their genetic profile, the ability to control environmental input, and the ability to conduct invasive procedures are all advantages in the use of animal

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models. Rodent models are broadly categorized into two types: those with spontaneous hair follicle abnormalities or disease, and those where genetic manipulation has been conducted to produce transgenic (gene overexpression) or knockout (gene inactivation) mice for a specific gene of interest [55]. Rodent models may be further classified based on the nature of the trait features they present. Rodent models available for hair biology and hair disorder research include those with: (1) a failure in hair follicle formation and consequently abnormally low numbers of hair follicles; (2) disorders of hair morphogenesis where hair follicles form but fail to fully develop; (3) hair follicle cycling disorders where hair follicles form and develop but fail to cycle correctly; (4) hair follicle structure and/ or sebaceous gland structure disorders often leading to hair shaft defects and alopecias; (5) disorders of hair fiber pigmentation; (6) immunological abnormalities resulting in alopecias; (7) neuroendocrine abnormalities; and (8) models of environmentally mediated diseases where exogenous factors are introduced to modify hair growth [44]. While there are perhaps a few hundred spontaneous murine hair-disorder models, since the introduction of transgenic technology literally thousands of genetically modified mice have been generated, many of which are probably relevant to understanding hair bio­logy and disease. Most regulatory events in hair follicle growth are conserved between rodents and humans. However, some critical differences have been described at the molecular level and animal models of hair disorders may not fully reflect the morphological presentation of disease in humans. Consequently, especially when it comes to the pathogenesis of human diseases, it is essential to carry out studies on human hair follicles in addition to animal model studies. There are of course numerous ethical limitations to experimental research directly on human volunteers. Typically, there are limited numbers of individuals willing to take part in research, their genetics are often unknown, their environment cannot be regulated, and invasive approaches are limited. However, as understanding human hair disorders is often the ultimate goal in hair research, studies with human volunteers are important. Where procedures cannot be conducted directly with humans, techniques have been developed to utilize human tissues. Transplant models, where diseased hair-bearing human skin is transplanted onto immunodeficient mice, provide a great opportunity to study and manipulate human hair growth. Skin transplantation to rodents has been used in research on androgenetic alopecia where no satisfactory rodent model is available, alopecia areata, and for the study of several forms of genetic trichoses. Immunodeficient mice have been extensively

 

used as hosts for tissue transplants or cell implantation to aid our understanding of basic hair biology. Such an approach, using tissue hosts, has significant advantages, particularly in the evaluation of drugs and their impact on hair growth. However, the approach also has some disadvantages. By isolating human tissue by grafting to a mouse host, the tissue is being removed from any systemic effects from elsewhere in the body; this is particularly relevant in inflammatory diseases. Plus, while biochemical signals in mice are often cross-reactive with human cell receptors this is not always the case. Consequently, a mouse host environment is somewhat different from a human hair follicle’s in situ environ. Culture techniques are a further option for functional research. Hair follicles contain readily identified cell populations of interacting cells that are clustered in discrete sites. Cell types can be isolated and continue to show pronounced interactive abilities when cultured in vitro. Primary cell cultures from murine and human hair follicles, including hair follicle keratinocytes, dermal papilla cells and melanocytes, provide important information on the expression of mediators and the behavior of single cell populations [8, 46]. They are, however, of more limited value, because they often lose their organ-specific characteristics within a few passages. As the knowledge on hair growth and its regulation becomes more and more complex, more sophisticated in vitro models are required which allow the investigation of the complex interactions during normal hair growth and in response to bioactive compounds. In this context, the whole-organ culture model first developed and described by Michael Philpott is a valuable tool [65]. Research conducted using animal models, “human models,” in vitro models, or perhaps in the future computer models, can each provide significant information. However, each approach has its limitations and rarely does just one model provide the complete picture. To fully understand hair biology and hair disease involves collating and assimilating information for all its diverse sources to piece together what is a very complex picture of hair biology.

1.12

Clinical Relevance

Before hair disorders can be studied, it is necessary to define the normal state of hair biology and hair growth. Without knowledge of what is a “normal” state one cannot characterize what is regarded as “abnormal.” The many evaluative studies on hair follicles, from the highly detailed studies of histologists over 150 years ago to the advanced genetic analysis of today, have revealed many secrets of normal hair follicle development, growth, and cycling. We now have a solid understanding of the es-

Biology of the Hair Follicle

sential principles of hair biology, though there is much more to learn. Major advances in our understanding of hair biology have helped to identify key pathogenetic events in common hair diseases including the altered androgen response and subsequent hair follicle miniaturization in androgenetic alopecia, or perifollicular inflammation involvement in alopecia areata and lichen planopilaris. Further, due to the complex interplay of signaling events in hair growth and cycling, hair follicles are extremely sensitive to endogenous influences, such as hormonal imbalances, systemic diseases, or nutritional defects. Environmental factors may also affect hair follicle growth, such as in response to stress or pathogens, or the impairment of mitotic activity caused by drugs resulting in changes in hair shaft caliber and breakage of hair fibers. Excessive or continuous exposure to toxins may induce massive impairment of hair growth leading to a loss of dystrophic anagen hair fibers. Information on hair biology, hair formation, and cycling is directly relevant to understanding the pathogenesis of clinically apparent hair disorders and the course of disease, not only for the trichologist but also for the patient. Communication of such information to the patient, apart from meeting the patient’s need for education on their disease, tremendously helps to improve compliance during treatment. For example, because of the hair growth kinetics, topical minoxidil treatment in androgenetic alopecia frequently requires regular application over the course of several months before a recovery of hair growth can be evaluated.

1.13

Outlook – Future Developments

Advances in molecular biology and gene expression profiling have led to a significant increase of knowledge about the genes and signaling pathways involved in hair growth and hair cycling. New insights into the complex regulation of hair follicles have led to a more finely defined understanding of the pathogenesis of diseases such as alopecia areata and androgenetic alopecia. Because current therapeutic concepts are still rather unspecific in their action, current research concentrates on the development of more focused strategies that will allow specific, targeted treatment of the various manifestations. Subgrouping of patients, by gene expression profiling for example, in the future may help to determine the most effective therapeutic option for each individual patient. The growing knowledge of the various signaling pathways involved in hair growth may further lead to the identification of new drug targets, opening the door for the development of novel drugs as, for example, with the

Chapter 1

development of biologicals for the treatment of psoriasis. The development of novel drug delivery systems that allow better penetration of active compounds into the hair follicles, and possibly targeting of specific compartments within the hair follicles, may allow an increase in the efficacy of established treatments and of new therapies with a reduction of side-effects. Last but not least, advances in stem cell isolation and purification may enable us to bioengineer hair follicles to provide efficient hair replacement therapy in cases where conventional treatments fail.

Summary for the Clinician Hair and hair follicles occur in a wide diversity all over the body except on the palms, soles, glabrous foreskin, and lip vermillion. Lanugo hair-producing hair follicles, vellus hair follicles, intermediate hair follicles, and terminal hair follicles can be identified. The hair follicle is a complex mini-organ in its own right. Each hair follicle is formed by multiple mesenchymal and epithelial cell layers, together comprising more than 20 different cell populations. Together with the sebaceous gland and the arrector pili muscle, the hair follicle is part of the so-called pilosebaceous unit. Relevant anatomical divisions can be made between the permanent, superficial structure and the transient cycling component of the hair follicle, which includes the hair bulb. The morphological dividing line between these two components lies below the bulge region, the putative site of epithelial stem cells and precursor populations of melanocytes, mast cells and Langerhans cells. Hair growth results from the proliferative matrix of keratinocytes that reside in the bulb, where they sit on the dermal papilla, a condensate of specialized mesenchymal cells with important inductive properties. Hair cycling is traditionally divided into a growth phase (anagen I–VI), a regression phase (catagen), and a resting phase (telogen). The shedding of the hair fiber has recently been identified as an active process of its own (exogen). The events of hair follicle morphogenesis and cycling are controlled by a complex network of sequential activation and inactivation of autocrine, paracrine, and endocrine signaling pathways. The hair follicle is surrounded by a dense meshwork of blood vessels and nerve endings. Multiple specialized cell populations can be found associated with the different compartments of the hair follicle, including melanocytes, neuroendocrine cells and immune cells.

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Chapter 2

2

The Endocrine Control of the Hair Follicle Valerie A. Randall

 

 

6

Synonyms hormone metabolism, hormonal control, endocrine metabolism of the hair follicle



Key Features

• Hair follicles can produce different types of hair

(length, thickness, colour) at various times in an individual’s life due to the follicle’s capacity to regenerate a new hair during the hair cycle. This allows hairs to change to correlate with alterations in season or sexual development, etc. The type of hair produced is under endocrine control with androgens being key regulators of human hair growth; several other hormones are involved, particularly in other mammals, including melatonin, prolactin, melanocyte-stimulating hormone (MSH) and oestrogens. Androgens have paradoxically different effects on human hair follicles depending on their body site. This ranges from stimulation, e.g. on the face, axilla, pubis and chest, through no effect on the eyelashes, to inhibition on parts of the scalp, causing balding in genetically susceptible individuals. All androgen effects require an intracellular androgen receptor in the hair follicle cells and most, except for pubic and axillary follicles, also require the intracellular enzyme 5α-reductase type 2 to metabolize testosterone to its more potent metabolite 5α- dihydrotestosterone.

• Exactly how androgens regulate hair follicles is not

fully established, but most aspects appear to be coordinated via the mesenchyme-derived dermal papilla situated at the base of the follicle. In the current hypothesis androgens from the blood bind to androgen receptors in dermal papilla cells, altering their gene expression, particularly of paracrine signalling molecules, which influence the activity of the other follicular cells. Key signals identified so far include insulin-like growth factor-1 (IGF-1) in growth stimulation and transforming growth factor-β (TGF-β) in inhibition. Androgen-dependent hair disorders are not easily controlled. Currently, antiandrogens, such as cyproterone acetate or spironolactone, can be used for hirsutism in women and 5α-reductase type 2 inhibitors, such as finasteride, for androgenetic alopecia. The most common non-endocrine treatment for hair loss is minoxidil, a vasoactive drug. Further understanding of the mechanism of androgen action in hair follicles should lead to the development of better treatments.

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•

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Contents 2.1 2.2 2.3 2.3.1

Introduction  . . . . . . . . . . . . . . . . . . . . . . . . . . History  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Structure and Function of Hair Follicles  . . Function  . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

  24   24   25   25

2.3.2 2.4

Changing the Type of Hair by the Hair Follicle Growth Cycle  . . . . . . . . . . . . . . . . . .   27 Endocrine Regulation of Seasonal Changes in Hair Growth  . . . . . . . . . . . . . . . .   27

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2.5 2.5.1 2.5.2 2.5.3 2.5.3.1

2.1

Animals  . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   27 Seasonal Variations in Human Hair Growth  . . . . . . . . . . . . . . . . . . . . . . . . . .   28 Hormonal Regulation of Human Hair Growth   . . . . . . . . . . . . . . . . . . . . . . . . .   28 Effects of Pregnancy  . . . . . . . . . . . . . . . . . . .   28 The Paradoxical Effects of Androgens on Human Hair Follicles  . . . . . . . . . . . . . . .   28 How Do Androgens Carry Out These Changes?  . . . . . . . . . . . . . . . . . . . . . . .   31 Current Model for the Action of Androgens in Hair Follicles  . . . . . . . . . . . . . . . . . . . . . . .   31

Introduction

The hair follicle, a highly unusual dynamic organ found only in mammals, is fascinating from many viewpoints. It is an essential mammalian characteristic important for warm bloodedness and for mammalian evolutionary success, and has an almost unique ability in mammals to regenerate itself, recapitulating many steps of embryogenesis as it does so [29] (see Chap. 1). In addition, in human beings it is a paradoxical tissue where the same hormones, the androgens, can cause stimulation of hair growth in many areas, e.g. beard, whilst simultaneously inhibiting hair follicles on the scalp causing balding [46, 50, 52]. Correctly functioning follicles are crucial to the survival of many mammals – loss of fur or faulty colouration may rapidly lead to death from cold or predation. Although hair loss is not life threatening for human beings, hair is very important for most people. Many Western men spend significant time every day shaving their beards, while hairdressers are everywhere and large amounts are spent on hair care. This reflects the very important roles hair plays in human communication, both in social and sexual contexts, and explains why hair growth disorders such as hirsutism, excessive male pattern hair growth in women, and hair loss {such as alopecia areata, an autoimmune disease affecting both sexes at all ages [49] (see Chap. 15)} cause serious psychological distress. Androgenetic alopecia or male pattern hair loss [51] (see Chap. 9) even causes negative effects among men who have never sought medical help. Hormones co-ordinate changes in the type of hair produced, usually in parallel with changes in the individual’s age and stage of development or alterations in the environment such as day length [9]. Hormones instruct the follicle to undergo appropriate co-ordinated changes so that during the next hair cycle the new hair produced differs in colour or size from that present originally. In human beings the key hormones are the

  2.5.3.2 2.5.4 2.5.5

2.5.6 2.6

Mechanism of Androgen Action in Hair Follicles  . . . . . . . . . . . . . . . . . . . . . . . Support for the Dermal Papilla-Based Model of Androgen Action  . . . . . . . . . . . . . Paracrine Factors in Mesenchymal– Epithelial Interactions in AndrogenRegulated Hair Follicles  . . . . . . . . . . . . . . . . Experimental Techniques  . . . . . . . . . . . . . . . Clinical Relevance and Conclusions, Outlook – Future Developments   . . . . . . . . Summary for the Clinician   . . . . . . . . . . . . .

  32   33

  33   35   36   36

References   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   37 androgens [46, 50, 52]. When androgens increase at puberty the development of more hair in the axilla and pubis in both sexes or on the face in men is welcomed as a sign of sexual maturity. However, if androgens stimulate hirsutism in women, or initiate androgenetic alopecia on the scalp, then the clinician’s aid is requested. Currently, available treatments for hair disorders, particularly androgen-dependent hirsutism and androgenetic alopecia, are rather limited and have widespread effects on the body. Greater understanding of how androgens alter the type of hair produced by the hair follicles should facilitate the development of more effective and selective treatments. This chapter will review the functions of hair, outline how the hair follicle growth cycle allows hairs to be changed and summarize the endocrine control of seasonal changes and pregnancy before focusing on how androgens act, predominantly on human hair follicles. Hormonal control of pigmentation will be covered in Chap. 4.

2.2

History

The importance of the testes for the development of normal hair growth was recorded by Aristotle 300 years B.C., well before the concept of hormones, i.e. soluble chemical messengers in the blood, was developed in the 1800s. In the mid 1900s an American anatomist, James Hamilton, clarified much of our current knowledge of androgens and human hair growth by comparing hair growth from childhood to old age in normal men and women from different genetic backgrounds and castrated men [17]. More recently the importance of the regulatory mesenchyme-derived dermal papilla at the base of the follicle in determining the type of hair produced [60] has led to the concept that hormones, particularly androgens, alter hair growth by acting via the dermal papilla to enable co-ordinated changes in the hair follicle [46, 50, 52].

The Endocrine Control of the Hair Follicle

2.3

2.3.1

Structure and Function of Hair Follicles Function

Mammalian skin produces hair everywhere except for the glabrous skin of the lips, palms and soles; human hair growth is less obvious in humans than in other mammals, with tiny, virtually colourless vellus hairs in many areas. Outside the skin hairs are thin, flexible tubes of dead, fully keratinized epithelial cells which are very variable in colour, length, diameter and cross-sectional shape; inside they form part of living hair follicles, cylindrical epithelial downgrowths into the dermis which enlarge into hair bulbs surrounding a mesenchyme-derived dermal papilla at the base (see Figs. 2.1, 2.2). In many mammals hair is important for insulation, an appropriate colour for camouflage and as a protective physical barrier, e.g. for ultraviolet light. Hair follicles are also sometimes specialized as neuroreceptors, e.g. whiskers, or for sexual communication, e.g. the lion’s

Fig. 2.1  Diagram of two hair follicle growth cycles where androgens cause the follicle and the hair it produces to become smaller. The gap between them represents other cycles not drawn. Hair follicles pass through regular cycles of growth (anagen), regression (catagen) and rest (telogen) during which the lower part of the follicle is regenerated and a new hair formed [29]. This permits the follicle to produce a different

Chapter 2

mane. In contrast, the main functions of human hair are protection and communication, although seasonal variation in human hair growth [7, 42, 53] and hair erection (goosebumps) in response to cold remain (reviewed [52]). The hairs seen in childhood are mainly protective: the eyebrows and eyelashes stop foreign bodies entering the eyes and scalp hair probably prevents sunlight, cold and physical damage to the head and neck. Scalp hair is also important in social communication. Other human hair is involved in sexual communication (reviewed [52]). Puberty is signalled by the development of pubic and axillary hair in both sexes (Fig. 2.3), while the sexually mature man exhibits masculinity by developing a beard and greater body hair on the chest, upper pubic triangle and limbs. The beard’s strong signal and its potential involvement in threatening display behaviour, like the lion’s mane, may explain its common removal in the less openly aggressive industrialized countries. Human hair’s important communication roles explain the serious psychological consequences and negative impact on the quality of life seen in hair disorders including androgenetic alopecia [14].

type of hair in response to hormonal stimuli to co-ordinate responses to changes such as sexual maturity or season. The new hair may differ in size and/or colour. The regenerated scalp hair follicles illustrated have responded to androgens by becoming smaller, protruding less far into the dermis and producing a smaller, less pigmented hair. Reproduced from Randall [48]

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  Fig. 2.2  Model of androgen action in the hair follicle. In the current model androgens from the blood enter the hair follicle via the dermal papilla’s blood supply. They are bound by androgen receptors in the dermal papilla cells causing changes in the cell’s production of regulatory paracrine factors; these then alter the activity of dermal papilla cells, follicular keratinocytes and melanocytes. (T Testosterone, ? unknown paracrine factors.) Reproduced from Randall [48]

Fig. 2.3  Human hair distribution under differing endocrine conditions. Visible (i.e. terminal) hair with protective functions normally develops in children on the scalp, eyelashes and eyebrows. During, and after, puberty additional terminal hair develops on the axilla and pubis in both sexes and on the face, chest, back and limbs in men. In people with the appropriate genetic tendency, androgens may also stimulate hair loss from the scalp in a patterned manner causing androgenetic alopecia. People with various androgen insufficiency syndromes (lower panel) demonstrate that none of this occurs without functional androgen receptors and that only the axillary and the female pattern of lower pubic triangle hairs are formed in the absence of 5α-reductase type 2. Male pattern hair growth (hirsutism) occurs in women with abnormalities of plasma androgens or from idiopathic causes and women may also develop a form of female androgenetic alopecia. Reproduced from Randall [48]

The Endocrine Control of the Hair Follicle

2.3.2

Changing the Type of Hair by the Hair Follicle Growth Cycle

To fulfil all these roles the hair produced by a follicle often needs to be changed via the follicle’s unique mechanism, the hair cycle (see Chap. 1). This involves destruction of the original lower follicle and its regeneration into another form which can produce a hair with different characteristics (Fig. 2.1). Exactly how different in size a hair can be to its immediate predecessor is currently unclear because many changes, such as production of a full beard or ear canal hair, take place over many years [17]. During each follicle’s frequent cycles hairs are produced in anagen, the growth phase [29]. Cell division takes place in the matrix of the hair bulb outside the dermal papilla, after which the keratinocytes move up into the thinner part of the follicle, differentiating into the layers of the hair and its surrounding sheaths. Melanocytes in the bulb also transfer pigment to the hair keratinocytes to give the hair colour. Anagen is followed by a short regression phase, catagen, when the fully keratinized “club” hair moves up in the skin and the lower follicle rests in telogen. When telogen ends the dermal papilla cells and associated keratinocyte stem cells reactivate, a new lower follicle develops and a new hair grows up into the base of the upper follicle; the existing hair is generally lost, either by the physical movement of the new hair or a further active shedding stage, exogen. The new hair may be very similar to its predecessor, like most human scalp hair, or may differ quite markedly, e.g. the brown summer and white winter hairs of arctic mammals or the Scottish mountain hare [52]. The type of hair produced depends on the regulatory dermal papilla [60] although the detailed cell biology and biochemistry of the local interactions are not fully understood. What is clear is that hair length is generally determined by the length of the anagen phase of the hair cycle; long scalp hairs are produced by follicles with anagen lasting over 2 years, while short finger hairs grow only for around 2 months [63]. This is, therefore, one of the main aspects regulated by hormones.

2.4

Endocrine Regulation of Seasonal Changes in Hair Growth

Hair follicles are under hormonal regulation, which brings about important co-ordinated changes in the insulative and colour properties of a mammal’s coat in response to the environment, or in hair visibility to sexual maturity. Seasonal changes usually occur twice a year in temperate regions, with co-ordinated waves of growth

Chapter 2

and moulting to produce a thicker, warmer winter coat and a shorter summer pelage [9, 31]. These changes are linked to day length and, to a lesser extent, to temperature in the same way as seasonal breeding activity (reviewed [52]).

2.4.1

Animals

Long daylight hours initiate short periods of daily melatonin secretion by the pineal gland and the summer coat in many species, while short (winter) day length increases melatonin secretion and a longer, warmer winter pelage develops [9, 52, 63]. The pineal gland acts as a neuroendocrine transducer converting nerve impulses stimulated by daylight to reduced secretion of melatonin, normally secreted in the dark. Melatonin signals are generally translated to the follicle via the hypothalamus–pituitary route, although melatonin appears also to act directly on prolactin secretion by the pituitary [31]. Prolactin is strongly implicated in follicular seasonal changes, although it is unable to carry out full hormonal cyclic regulation in the absence of other pituitary hormones or the hormones they regulate in other endocrine organs, e.g. the gonadotrophins and sex steroids; insulin-like growth factor-1 (IGF-1) may also be involved (reviewed [52]). Increased circulating prolactin levels in periods of long daylight correspond to low summer hair growth, while the low prolactin concentrations observed in short days correspond with increased winter hair growth in many species. Prolactin receptors are seen in rodent and mink skin and the key dermal papilla and sheep hair follicles and infusion of local prolactin in vivo also inhibits local hair growth in goats. Interestingly, prolactin messenger ribonucleic acid (mRNA) is also expressed in hair follicles of several species suggesting that prolactin is produced as a local paracrine factor. Other hormones implicated in regulation of the hair growth cycle include the sex and adrenal steroids, which delay anagen in rats (whereas gonadectomy and adrenalectomy advance it), and thyroid hormones, which advance anagen [9, 52]. Interest in oestrogen’s effects on hair growth has reactivated recently. Topical, i.e. external, application of 17β-oestradiol to mice skin inhibits hair growth and accelerates catagen, while antioestrogens promote early anagen [4, 41]. Oestrogen receptors alpha (ERα) and beta (ERβ) have been located in human hair follicles [69] and cultured dermal papilla cells by immunocytochemistry and reverse transcriptase polymerase chain reaction (RT-PCR) [68]. How all these circulating hormones interact is still not clear, but the main drivers of light, melatonin and prolactin are now well established in the control of seasonal coat changes.

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2.4.2

2

Seasonal Variations in Human Hair Growth

Seasonal changes are less obvious in human beings, where follicle cycles are generally not synchronized with their neighbours except in local groups of three follicles called Demeijère trios [63]. Regular annual cycles in human scalp and beard and other body hair have only been fully recognized relatively recently [7, 42, 53]. Men and women in northern temperate regions exhibit an autumnal moult of scalp hair. Since scalp hair usually grows for 2–3 years or longer [29, 63], it is remarkable that any annual cycle is apparent at all. Randall and Ebling [53] found that beard and thigh hair growth rate was low in the winter in 14 Caucasian men, but increased significantly in the summer (Fig.  2.4). Similar summer peaks of semen volume, sperm count and sperm mobility were reported in 260 French men [58], whose luteinizing hormone (LH), testosterone and 17β-oestradiol levels peaked in the autumn; smaller studies also reported low testosterone in the winter and higher levels in summer in European men and pubertal boys (reviewed [17]). Testosterone changes probably alter beard and thigh hair-growth rate, but whether they regulate scalp follicles is less clear as most scalp hair growth is not androgen-dependent and seasonal effects are also seen in women. However, androgens do inhibit scalp follicles in certain areas of genetically susceptible individuals, causing balding [16], and low levels of androgen receptors are present in cultured dermal papilla cells [57] derived from non-balding scalp follicles, making such a response feasible. In contrast to single annual cycles on the scalp and beard, there are biannual changes in the number of follicles actually growing hair on the thigh [17]. This biannual pattern resembles the spring and autumn moults seen in many temperate mammals and may remain from earlier in our evolution. Presumably these cycles are controlled in a similar way to those described in Sect. 2.4.1 for other mammals. Human beings do retain the ability to respond to changes in day length by altered secretion of melatonin, prolactin and cortisol, but urban environments in which light and dark are artificially manipulated probably suppress these responses [73]. Nevertheless, people living in the Arctic and those with seasonal affective disorder maintain melatonin rhythms and our study population definitely maintained seasonal behaviour patterns (reviewed [52]). In addition to demonstrating that human beings in temperate zones are still seasonal mammals, these pronounced annual changes have an important significance for any investigations of human scalp or androgen-dependent hair growth. These are parameters which are often measured in assessments of new therapies; to be accurate measurements should be carried out over a full

 

year, otherwise results will be very difficult to interpret due to the endogenous variation.

2.5

Hormonal Regulation of Human Hair Growth

Apart from the seasonal changes described in Sect. 2.4.2, the most obvious regulators of human hair growth are the androgens, as long as an individual has good nutrition and normal thyroid function (reviewed [52]); hypothyroidism is normally associated with hair loss [10]. Pregnancy also has effects on hair growth with diffuse hair loss after the birth, a well established clinical phenomenon.

2.5.1

Effects of Pregnancy

Lynfield [34] found that more scalp follicles were in anagen during the second and third trimesters of pregnancy (95%) and for about a week after the birth. By 6 weeks this had fallen to only about 76% and remained low for 3 months. Pregnancy hormones maintain follicles in anagen, but after the birth many enter catagen and telogen, resulting in a synchronized partial shedding or moult. This is likely to be particularly noticeable if it coincides with the autumnal increase in shedding (Sect. 2.4.2). Which hormones are involved is uncertain, although oestrogens and prolactin are possibilities and human follicles have receptors for both prolactin [13] and 17β-oestradiol [68, 69]. However, 17β-oestradiol inhibits hair growth and accelerates the start of catagen in rodents [4, 41], and inhibits cultured scalp follicles [6], the opposite effect to pregnancy. Prolactin also inhibits cultured human follicles [13], which could support a role in post-partum shedding.

2.5.2

The Paradoxical Effects of Androgens on Human Hair Follicles

Androgens’ dramatic stimulation of human hair growth manifests initially in puberty with the development of pubic and axillary hair in both sexes [35, 36], occurring later in boys than girls in parallel with rising plasma androgens. Further evidence comes from testosterone’s ability to stimulate beard growth in eunuchs and elderly men [5], and the inhibition of beard [17] and male pattern baldness [18] by castration. However, the strongest support comes from individuals with complete androgen insufficiency, i.e. without functional androgen receptors [38]. These XY individuals develop a female phenotype, as they are unable to respond to androgen.

The Endocrine Control of the Hair Follicle

Chapter 2

Fig. 2.4a,b  Seasonal changes in androgen-dependent human hair growth. British men exhibit marked seasonal changes in hair growth in several parts of the body [53]. Beard (a) and thigh hair (b) grows significantly faster in the summer months and more slowly in the winter, even when the men have indoor

occupations. Measurements are the mean ±SEM for Caucasian men (13 beard, 14 thigh) from northern England. Statistical analysis was carried out using runs (RT), turning points (TP) and phase length (PL) tests. Data from Randall and Ebling [53], redrawn for [50]

However, their female phenotype is incomplete as they do not develop even female patterns of pubic or axillary hair (Fig. 2.3, lower panel). Growth hormone is also required for the full androgen response, as sexual hair development is inhibited in growth hormone deficiency (see [52]). Androgens stimulate the tiny vellus follicles that produce fine, virtually colourless and almost invisible hairs to transform into larger, deeper follicles forming longer, thicker, more pigmented hairs (Fig. 2.5, upper panel); they do this by passing through the hair cycle to regenerate a new follicle to carry out such changes (Fig. 2.1). Although androgens stimulate hair growth in many areas, being responsible for the greater amount of body hair on the face, upper pubic diamond, chest and limbs, etc. in adult men [17], they can also have the opposite effect on specific areas of the scalp, often in the same individual, causing loss of terminal hair and balding [16]. This involves the reverse transformation of the large, deep follicles that produce very long, often heavil­y pigmented terminal scalp hairs to miniaturized vellus follicles that form tiny, almost invisible hairs (Figs. 2.1, 2.5). This usually occurs in a precise pattern starting with regression on the forehead and thinning in the centre of the vertex and may continue to expose large areas of scalp [16]; the lower sides and back of the scalp normally retain terminal hair (Fig. 2.3, upper panel). Androgenetic alopecia is reviewed Chap. 9 and elsewhere [51]. Similar hair loss,

which is considered androgen-dependent, can occur in women, but the pattern differs (Chap.  10). In women, the frontal hairline is normally retained and progressive generalized thinning occurs on the vertex until it appears bald [33]. In contrast, androgens appear to have no effect on other hairs such as the eyelashes. This is a biological paradox. How does one hormone stimulate the hair follicle in many areas, have no effect in another, while causing inhibition in the same organ in a different part of the body, often in the same individual? Interestingly, there are other differences between follicles which all respond to androgens with increased growth. Axillary and lower pubic follicles enlarge in response to female levels of androgens, while other follicles require male levels [35, 36]. Follicles also differ in their sensitivity, or speed of response. In boys and hirsute women facial follicles alter initially above the mouth and on the chin; eventually this spreads over the face and parts of the neck [35, 36]. This progression resembles the patterned progression of androgenetic alopecia. Many androgen responses are gradual, with some follicles taking years to manifest their full response. Beard weight increases dramatically during puberty but continues to rise until the mid-thirties, while terminal hairs may only be visible on the chest or external ear canal years after puberty [17]; the miniaturization processes of androgenetic alopecia also continue well into old age [16]. This delay parallels the late onset of

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2

Fig. 2.5  Androgens have paradoxically different effects on human hair follicles depending on their body site. During and after puberty androgens stimulate the gradual transformation of small follicles producing tiny, virtually colourless, vellus hairs to terminal follicles producing longer, thicker and more pigmented hairs (upper panel) [8]. These changes involve passing through the hair cycle (see Fig. 2.1). At the same time many follicles in the scalp and in the eyelashes continue to produce the same type of hairs, apparently unaffected by androgens (middle panel). In complete contrast, androgens may inhibit follicles on specific areas of the scalp in genetically susceptible individuals causing the reverse transformation of terminal follicles to vellus ones and androgenetic alopecia [16]. Diagram reproduced from Randall [48]

The Endocrine Control of the Hair Follicle

androgen-dependent benign prostatic hypertrophy and prostatic carcinoma. Another demonstration of the individual behaviour of follicles from different sites is the contrasting growth patterns of beard and axillary hair. Although both increase rapidly during puberty in Caucasians and Japanese men, beard growth remains heavy into old age, while axillary hair growth falls rapidly in both sexes and races after the mid-twenties [17]. This is another paradox: why do follicles in some areas no longer show their androgenic responses, while in many others they maintain or extend them? All these contrasts must be due to intrinsic differences in gene expression within follicles at different sites, since all are exposed to the same circulating hormones. A follicle’s retention of its original androgen response when transplanted confirms this [43]. Presumably, this genetic programming occurs during the patterning processes during development. The molecular mechanisms involved in the formation of different types of follicles during embryogenesis are not clear, but may include secreted signalling factors, such as Eda, sonic hedgehog, Wnt and various growth factor families (e.g. the BMPs), nuclear factors (including various homeobox genes), and others such as Hairless and Tabby, plus transmembrane and extracellular matrix molecules [40, 75]. Human follicles need androgen exposure not only for the initial transformations, but also to maintain many effects. If men are castrated, beard growth falls but neither beard growth nor male pattern baldness returns to prepubertal levels [16, 17], suggesting that some of the altered gene expression does not require androgens to maintain its effects. However, beard growth is enhanced in the summer, probably in response to increased circulating androgens (Sect.  2.4.2), antiandrogen treatment reduces hair growth in hirsutism and another blocker of androgen action, the 5α-reductase type 2 inhibitor finasteride, can cause regrowth in androgenetic alopecia [28]. This suggests that androgens are required to maintain most of the response, as well as to initiate progression. The intrinsic differences in hair follicle responses to androgens depending on their body site have an important consequence for anyone wishing to investigate androgen action in human follicles. It is essential to study follicles which respond appropriately in vivo for the question being addressed. Unfortunately, this means that the most usually available material, non-balding scalp, is inappropriate for many experiments. Genetics play important roles in androgen-dependent hair growth (reviewed [52]). Male pattern baldness and heavy beard growth run in families: Caucasians generally have greater hair growth than the Japanese, despite similar testosterone levels, and men of African descent exhibit much less androgenetic alopecia. Interestingly, both women with polycystic ovaries and their brothers

Chapter 2

with early androgenetic alopecia showed a link to one allele of the steroid metabolism gene, CYP17 [3]. However, no association was seen in men with androgenetic alopecia and genetic markers for the genes for 5α-reductase enzymes involved in metabolizing testosterone to the more potent 5α-dihydrotestosterone. Some changes in the androgen receptor were more frequent in balding men [12] and androgen receptors from girls with precocious puberty, i.e. early pubic hair, showed a smaller number of CAG repeats than controls [23]. Whether this has functional significance such as increased androgen sensitivity or simply reflects linkage disequilibrium with a causative mutation is unclear. However, the similar steroid-binding capacity of androgen receptors from balding and non-balding follicle dermal papilla cells does not support increased sensitivity [20].

2.5.3

How Do Androgens Carry Out These Changes?

Androgens have to alter many aspects of follicular cell activity to change the type of hair produced. They have to change the division capacity of epithelial matrix cells, determine whether they should differentiate into medulla (a central part of the hair found in large hairs) and regulate the amount of pigment that is produced by the follicular melanocytes and/or transferred to the differentiating keratinocytes to determine hair colour. They also have to alter dermal papilla size, since this maintains a constant proportion to the hair size [11, 72], and the connective tissue or dermal sheath, which surrounds the follicle, must expand to accommodate a larger follicle. Androgens definitely alter these aspects of hair follicle activity, as antiandrogen treatment reduces diameter, rate of growth, hair length, pigmentation and medullation in hirsute women [64], whereas blocking 5α-reductase activity increases many aspects in androgenetic alopecia [28]. The remaining question is whether androgens act on each target cell individually or through one co-coordinating system with indirect effects on other cell types.

2.5.3.1 Current Model for the Action of Androgens in Hair Follicles Since androgen-potentiated changes are complex but there is little evidence of abnormalities, the processes must be highly controlled. This suggests that androgen action is co-coordinated through one part of the follicle. The current hypothesis, proposed in the early 1990s [56] (reviewed [46, 50, 52]), focuses on the dermal papilla. In this androgens act directly on the dermal papilla cells, binding to their androgen receptors and initiating al-

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tered gene expression of regulatory factors which influence the other target cells (Fig. 2.2); these factors could be soluble paracrine factors and/or extracellular matrix factors. This model makes the dermal papilla the key direct target, while other cells such as keratinocytes and melanocytes are indirect androgen targets. Some recent observations suggest minor modifications to this model. The dermal sheath which surrounds the hair follicle is now thought to play an important role in the hair follicle. The lower sheath can form a new dermal papilla and stimulate new hair follicle development [61]. Cultured dermal sheath cells from beard follicles contain similar levels of androgen receptors to beard dermal papilla cells (Merrick et al. unpublished observations) and balding scalp dermal sheath also expresses the mRNA for 5α-reductase type 2 [2]. The sheath may function as a reserve to replace the key inductive and controlling role of dermal papilla cells if they are lost, because of the essential role of hair for survival in many mammals. Dermal sheath cells may also respond directly to androgens to facilitate alterations in sheath, or even dermal papilla, size in the formation of a new anagen follicle. Recently, a very specialized keratin, hHa7, was found in the central medulla of beard, pubic and axillary hairs [27]. Beard medulla cells showed co-expression of keratin hHa7 and the androgen receptor. Since the hHa7 gene promoter also contained sequences with high homology to the androgen response element (ARE), keratin hHa7 may be regulated by androgens. However, when the promoter was transfected into prostate cells there was no stimulation. Although this could be due to inhibitors in the prostate cells, keratin hHa7 with the same promoter is also expressed in androgen-insensitive body hairs of chimpanzees [27]. The full significance of these observations is not yet clear, but androgens may also stimulate medullary cells directly. These results merit a modification of the model to include a possible specific, direct action of androgens on the cells of the lower dermal sheath and medulla cells.

2.5.3.2 Mechanism of Androgen Action in Hair Follicles Androgens, like other steroid hormones, act on target cells by diffusing through the plasma membrane and binding to specific intracellular receptors (Fig. 2.6). On binding the relevant steroid, the receptor complexes undergo a conformational change exposing DNA binding sites and, often in association with accessory proteins and co-factors, bind to specific hormone response elements (HRE) in the DNA, promoting the expression of specific, hormone-regulated genes [19]. The mechanism

 

Fig.  2.6  Simple schematic of the general mechanism of androgen action. Androgens diffuse from the blood through the plasma membrane. Inside the cell, like other steroid hormones, testosterone may bind to specific androgen receptors (upper scheme). This appears to occur in many tissues such as skeletal muscle and axillary and pubic hair follicles. However, in certain tissues, particularly the secondary sexual organs such as prostate or beard and balding hair follicles, testosterone is metabolized to the more potent androgen 5α-dihydrotestosterone (lower scheme). If both are available in similar quantities the receptor will bind 5α-dihydrotestosterone. Once hormone has bound, the receptor complex undergoes a conformational change exposing DNA binding sites and the hormone-receptor complex, in conjunction with other co-activating proteins, will bind to specific hormone response elements (HREs) in the DNA altering the expression of specific androgen-dependent genes

for androgens is more complex than those of other steroids. In some tissues, such as skeletal muscle, testosterone, the main circulating androgen in men, binds the receptor. However, in many tissues, including the secondary sexual tissues such as the prostate, testosterone is metabolized intracellularly by one of the 5α-reductase enzymes to 5α-dihydrotestosterone, a more potent androgen, which binds preferentially and more strongly to the androgen receptor to activate gene expression [47] (Fig. 2.6). All androgen-dependent follicles require the androgen receptor to respond, as demonstrated by the absence of adult body hair in complete androgen insensitivity (Fig.  2.3), the natural human “knock-out” model for the androgen receptor [38]. In contrast, the need for 5α-reductase activity varies with follicle site. Individuals with 5α-reductase type 2 deficiency only produce female patterns of pubic and axillary hair growth after puberty, although their body shapes become masculinized [74] (Fig. 2.3); 5α-reductase type 1 deficiency has never been reported. This suggests that 5α-dihydrotestosterone is

The Endocrine Control of the Hair Follicle

necessary for the responses of all the male-specific hair follicles including the beard, chest and upper pubic triangle, while testosterone itself can stimulate the axilla and lower pubic triangle follicles characteristic of adult women. Since people with 5α-reductase type 2 deficiency do not show androgenetic alopecia and the 5α-reductase type 2 inhibitor, finasteride, can restore hair growth in male pattern baldness [28], 5α-reductase type 2 also seems to be important for androgen-related balding. It is unclear why some follicles need 5α-dihydro­ testosterone while others need testosterone to carry out the alterations in gene expression required to cause the same types of cell biological changes that lead to a larger hair; it seems likely that the cells use different intracellular coactivating proteins to act with the receptor. This is yet another paradox of androgen action in human hair follicles. The skin and hair follicles contain a range of enzymes that can metabolize weak androgens, such as circulating dehydroepiandrosterone from the adrenals, to the more powerful testosterone, or potent androgens such as testosterone and 5α-dihydrotestosterone to the oestrogens 17β-oestradiol or oestrone (see Fig. 2.7). The lack of hair in complete androgen insufficiency syndrome demonstrates that the androgen receptor is crucial for

Fig. 2.7  Androgen metabolism. Circulating androgens such as testosterone from the testis in men and weaker androgens such as dehydroepiandrosterone and androstenedione from the adrenals and ovaries in women can be metabolized in many skin tissues. Some metabolism causes an increase in potency, e.g. from testosterone to 5α-dihydrotestosterone, as the androgen receptor binds 5α-dihydrotestosterone more strongly even than testosterone, another potent androgen. Other metabolisms form weaker androgens normally involved in excretion pathways, e.g. the androstanediols or steroids which act via the other steroid receptors, i.e. the oestrogens

Chapter 2

such hair growth; therefore, the androgens that bind most strongly to the receptor, namely testosterone and 5α-dihydrotestosterone, must be the most important.

2.5.4

Support for the Dermal PapillaBased Model of Androgen Action

The key molecules for this model, androgen receptors, have been localized by immunohistochemistry in the dermal papilla and by protein binding assay in cultured dermal papilla cells derived from androgen-sensitive follicles such as the beard, balding scalp and red deer mane (reviewed [52]). Cells from androgen-sensitive sites contain higher levels of specific, saturable androgen receptors compared to androgen-insensitive nonbalding scalp in vitro [1, 20, 57]. Most importantly, testosterone metabolism by cultured dermal papilla cells also reflects hair growth in patients with 5α-reductase deficiency; beard, but not pubic or non-balding scalp cells form 5α-dihydrotestosterone in vitro (reviewed [52]). This has led to wide acceptance of the hypothesis.

2.5.5

Paracrine Factors in Mesenchymal– Epithelial Interactions in AndrogenRegulated Hair Follicles

The final part of the model involves the alteration of paracrine signalling factors by dermal papilla cells. Cultured dermal papilla cells secrete extracellular matrix factors and also soluble, proteinaceous growth factors which stimulate the growth of other dermal papilla cells, outer root sheath cells and transformed epidermal keratinocytes (reviewed [52]). Soluble factors from human dermal papilla cells can cross the species divide and affect the growth of rodent cells in vitro and in vivo [15] (Fig. 2.8), paralleling the ability of human dermal papillae to induce hair growth in vivo when implanted into transacted follicles of athymic mice [26]. Importantly, physiological levels of testosterone in vitro increased the mitogenic capacity of beard cells to affect beard dermal papilla cells, outer root sheath cells and keratinocytes and decreased that of androgenetic alopecia dermal papilla cells from men and stump-tailed macaques in line with the hypothesis (reviewed in [52]). This implies that an autocrine mechanism of producing paracrine factors for beard cells is involved in androgen-stimulated beard cell growth. Certainly, the size of the dermal papilla is proportional to the size of the hair [11, 72] and androgen-mediated changes involve an alteration in dermal papilla cell numbers as well as the amount of extracellular matrix present [11]. A need to modify the autocrine production of growth factors after androgen stimulation

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Fig. 2.8  Androgenetic alopecia dermal papilla cells secrete soluble factors in culture which delay rodent hair growth in vivo. Conditioned media produced by dermal papilla cells cultured from normal, lesional edges (termed clinically normal) and balding scalp hair follicles and control media were injected into mice (n=5 or 6) when the follicles were resting. Although normal dermal papilla cell media had little effect, media from both lesional edge and balding cells inhibited the start of anagen in the mice demonstrating an inhibitory effect caused by soluble factors produced by human dermal papilla cells which could cross the species divide. Data from Hamada and Randall [14]

could contribute to the slow androgenic response, which often takes many years to reach full effect. As well as supporting the hypothesis for the mechanism of action, these results demonstrate that the paradoxical effects of androgen on hair follicles observed in vivo are reflected in vitro, strengthening the use of cultured dermal papilla cells as a model system for studying androgen action in vitro. The main priority now lies in identifying specific factors whose production is altered by androgens either in beard cells as an example of androgen-stimulated follicles or in androgenetic alopecia cells for inhibition effects. There is great interest in paracrine signalling in developing and cycling follicles (e.g. [59]), but to date only insulin-like growth factor (IGF-1) has been identified as secreted by beard dermal papilla cells under androgen stimulation in vitro [25]. IGF-1 is a potent mitogen and maintains anagen in cultured scalp follicles [45]; when its effects are blocked in the

 

IGF-1-receptor-deficient mouse abnormal patterns of hair follicle growth and differentiation occur [32]. Stem cell factor (SCF, also known as mast cell growth factor, c-kit ligand or Steel factor) is secreted in greater quantities by beard than non-balding scalp cells, although androgens in vitro do not alter its production [21]. As SCF, the ligand for the melanocyte receptor c-kit, plays important roles in the development of epidermal and hair pigmentation, the dermal papilla may be the local source of SCF for follicle melanocytes. Beard cells’ greater production of SCF indicates that in vivo androgens had increased scf gene expression by facial dermal papilla cells to cause the hair darkening seen when beard develops. DNA microarray methods, which facilitate comparison of the genes expressed under different conditions, also revealed different gene expression between beard and normal scalp dermal papilla cells, with three genes, sfrp-2, mn1 and atp1β1, expressed at higher levels in beard cells, but no changes due to androgen in vitro [62]. Although dermal papilla cells from androgenetic alopecia areas are even more difficult to culture than those from normal scalp follicles [54], studies using these cells have also produced some interesting results. Androgens inhibit gene expression of the protease nexin-1 in cells derived from balding hair follicles [65]. Protease nexin-1, also known as glia-derived nexin-1, is a potent inhibitor of serine proteases such as thrombin, urokinase and plasmin, thereby regulating cellular growth and differentiation in many tissues. Since its effect in other tissues is modulated by extracellular matrix components such as type IV collagen, which dermal papilla cells also produce, alterations in protease nexin-1 production by dermal papilla cells could change their production of such extracellular matrix components and therefore the size of the follicle and hair produced. Androgens also stimulate the production of another commonly inhibitory factor, transforming growth factor-β (TGF-β), by a line of cultured androgenetic alopecia dermal papilla cells with “knocked-in” androgen receptors [24], and of TGF-β2 by two of four natural androgenetic alopecia cells [22]. TGF-β is a strong candidate for a role in inhibiting keratinocyte activity in androgenetic alopecia (reviewed in [52]). Follicular keratinocytes have receptors for TGF-β and it inhibits human hair follicle growth in vitro [44] and induces catagen in human beings and mice, while a probable suppressor of TGF-β1 delays catagen progression in mice in vivo. However, when gene expression in cultured dermal papilla cells was compared using DNA macroarray analysis TGF-β2 and TNF-α were actually slightly reduced in balding cells [39]. This could reflect the limitations of using a single control sample of nonbalding dermal papilla cells for a comparison with cells from four people with androgenetic alopecia.

The Endocrine Control of the Hair Follicle

Media conditioned by dermal papilla cells from balding scalp follicles also inhibited the growth of both human and rodent whisker dermal papilla cells in vitro and delayed mouse hair growth in vivo (Fig. 2.8) [15]. The results suggest the active secretion of an inhibitory factor or factors. Transforming growth factor β is unlikely to be involved as it is associated with the transition from anagen to catagen, it does not delay the onset of anagen, and receptors for TGF-β are only in follicular keratinocytes, not the dermal papilla cells responding here (reviewed [15, 52]). Another inhibitory factor, interferon-β, was secreted by a single line of SV-40 transformed normal scalp dermal papilla cells whose media suppressed the growth of outer root sheath cells [30]. However, the significance of this is unclear as these were normal scalp cells, not balding ones, and normal scalp medium usually stimulates cell growth. Further studies of paracrine factors produced by dermal papilla cells under androgen stimulation should clarify these control pathways and thus lead to better treatments.

2.5.6

Experimental Techniques

Studying androgen action in hair follicles is hampered by the lack of good, readily available and easy to use experimental models. Human hair follicles are the best tissue for investigating androgen mechanisms of action, but it is not ethical to carry out much research on people other than noninvasive observations, e.g. studying seasonal changes, or clinical trials of new therapies. Unfortunately, there are also great difficulties when considering animal models for investigating androgen action (reviewed [55]). For example, the Wistar laboratory rat and the black mouse C57BL/6, used to study many aspects of hair growth, are not suitable for investigating androgen action because there are major differences in function and hormonal regulation between human beings and other mammals. The androgen-dependent manes of lions (Panthera leo) and red deer (Cervus elaphus) are the most likely mammalian parallels for a man’s beard, but neither is practical for in vivo studies. More useful in vivo models include specialized androgen-sensitive follicles, such as those of the hamster costovertebral gland (a secondary sexual tissue involved in social communication), and mice with immunological deficiencies, e.g. nude (Foxn1nu/Foxn1nu) mice, which are unable to reject foreign skin and are used in special aseptic environments to accept human skin grafts from androgenetic alopecia [71]. Androgen-dependent hair loss in the androchronogenetic alopecia mouse [37] and, particularly, the stump-tailed macaque [70] has been harnessed to investigate novel treatments for androgenetic alope-

Chapter 2

cia. However, both are somewhat different from human balding and the effect is seen in both sexes. In vitro models generally offer the best opportunity to investigate human follicles since isolated cells, follicles or skin samples can be readily cultured from small samples of human skin. Limited amounts of human tissue are available for in vitro studies, but this is frequently a surgical by-product and may not be appropriate to answer particular questions such as how androgens act in follicles from different sites. Primary cultures of various individual cell types have been studied (reviewed [55]). These allow assessment of the features of individual cell types with or without manipulation in vitro, investigation of the interactions of the various cell types in vitro, or re-implantation of the cells in vivo in rats, nude mice or even people. Such studies have provided important information about the roles of dermal papilla cells and indicate that the dermal sheath can take over the inductive roles of the dermal papilla [61]. Such cultured cells have serious disadvantages including the short-lived nature of primary cultures, the absence of their normal cellular interactions, physical constraints and their natural environmental supplies of nutritive and regulatory factors. Some of these disadvantages are overcome by organ culture of isolated follicles [45], which achieves more normal cellular interactions between many cell types; the follicles can synthesize new hair in vitro, while still retaining the ability to be manipulated in vitro. However, these are still short-lived and the limited types of human follicles available have prevented this approach from being used much for androgen studies. Culture of whole skin biopsy samples theoretically overcomes the limitations on cellular interactions and physical constraints, but there are difficulties in ensuring penetration of nutrients, etc. and in understanding what is happening in which part of the skin. Practical in vitro models for studying androgen action include human dermal papilla cells and similar cells and whole hair follicles from red deer, which have androgen-dependent manes. Red deer are killed for food and large numbers of follicles are available from one individual; follicle organ culture and dermal papilla cells have both been studied successfully [8, 67]. Fortunately, cultured human dermal papilla cells from hair follicles with different sensitivities to androgens offer a useful model with which to study the effects of androgens [55]: the dermal papilla cells play a central role; they can be grown from small samples of human tissue; they can stimulate hair growth in vivo at low passage numbers [60]; and they retain characteristics in vitro which reflect their responses to androgens in vivo.

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2

Clinical Relevance and Conclusions, Outlook – Future Developments

Understanding the hormonal regulation of human hair growth has important relevance to the clinician as the most common hair disorders, androgenetic alopecia and hirsutism, are potentiated by androgens. All androgen effects need androgen receptors in the follicle and many, but not all, require the intracellular metabolism of testosterone to the more potent 5α-dihydrotestosterone. This means that antiandrogens should block all androgen effects on hair growth, while 5α-reductase inhibitors should be more selective at inhibiting beard growth and balding but not axillary or female patterns of hair growth. Antiandrogens have unacceptable side-effects in men and both antiandrogens and 5α-reductase inhibitors are contraindicated in women of child-bearing age as they may feminize a male fetus. In the current model for androgen action, the mesenchyme-derived dermal papilla in the hair bulb plays a central role in responding to androgens by altering its production of paracrine regulators which coordinate changes in follicular cells such as the keratinocytes which make the hair. Future research needs to focus on identifying these paracrine factors; understanding these should enable the development of more specific, focused treatments for both men and women which could hopefully be applied topically to reduce side-effects. Recently, a successful response to a 5α-reductase inhibitor, finasteride, was related to the increased expression of IGF-1 by the dermal papilla during treatment [66]; this provides clinical evidence of the importance of dermal papilla-produced paracrine factors and emphasizes the key role of the dermal papilla in androgen action.

 

Summary for the Clinician The hair follicle is a dynamic organ able to regenerate new and different hairs under hormonal regulation to coordinate hair type with season, age or sex. Androgens are the main regulator of human hair growth with paradoxical differences in follicular responses depending on their body site; these range from stimulation, e.g. beard, through no effect on eyelashes to inhibition on the scalp. Follicles retain these different responses when transplanted – the basis of corrective cosmetic surgery for androgenetic alopecia. Androgens potentiate important hair disorders including hirsutism and androgenetic alopecia acting via intracellular androgen recep-tors and 5α-reductase type 2 enzymes to alter gene expression within the follicle. These conditions are currently difficult to treat due to the unacceptable broad side-effects of antiandrogens in men, which block all androgen actions. 5α-reductase inhibitors, such as finasteride, seem appropriate in men because they selectively reduce testosterone metabolism to the more potent 5α-dihydrotestosterone and therefore should only affect tissues such as beard and balding follicles and the prostate. Neither is suitable for women of reproductive age due to the risk of feminizing a male fetus. Further research on the local signalling molecules altered by androgens in the regulatory dermal papilla of androgen-sensitive follicles may identify more selective targets for new therapies. When investigating new treatments in patients investigators need to remember the seasonal changes in human hair growth which affect scalp and androgen-stimulated growth.

The Endocrine Control of the Hair Follicle

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Hamada K, Randall VA (2006) Inhibitory autocrine factors produced by the mesenchyme-derived hair follicle dermal papilla may be a key to male pattern baldness Br J Dermatol 154:609–618 16. Hamilton JB (1951) Patterned loss of hair in man; types and incidence. Ann NY Acad Sci 53:708–728 17. Hamilton JB (1958) Age, sex and genetic factors in the regulation of hair growth in man: a comparison of Caucasian and Japanese populations. In: Montagna W, Ellis RA (eds) The biology of hair growth. Academic Press, New York, pp 399–433 18. Hamilton JB (1960) Effect of castration in adolescent and young adult males upon further changes in the proportions of bare and hairy scalp. J Clin Endocrinol Metabol 20:1309–1318 19. Handelsman D J (2005) Androgen action and pharmacologic uses. In: DeGroot LJ, Jameson J L (eds) Endocrinology, 5th edn. WB Saunders, Philadelphia, pp 3121–3138 20. Hibberts NA, Howell AE, Randall VA (1998) Dermal papilla cells from human balding scalp hair follicles contain higher levels of androgen receptors than those from non-balding scalp. J Endocrinol 156:59–65 21. Hibberts NA, Messenger AG, Randall VA (1996) Dermal papilla cells derived from beard hair follicles secrete more stem cell factor (SCF) in culture than scalp cells or dermal fibroblasts. Biochem Biophys Res Commun 222:401–405 22. Hibino T, Nishiyama T (2004) Role of TGF-β2 in the human hair cycle. J Dermatol Sci 35:9–18 23. Ibanez L, Ong KK, Mongan N et al (2003) Androgen receptor gene CAG repeat polymorphism in the development of ovarian hyperandrogenism. J Clin Endocrinol Metab 88:3333–3338 24. Inui S, Fukuzato Y, Nakajima F et al (2002) Androgeninducible TGFbeta1 from balding dermal papilla cells inhibits epithelial cell growth: a clue to understand paradoxical effects of androgen on human hair growth. FASEB J 16:1967–1969 25. Itami S, Kurata S, Sonada T et al (1995) Interactions between dermal papilla cells and follicular epithelial cells in vitro: effect of androgen. Br J Dermatol 132:527–532 26. Jahoda CA, Oliver RF, Reynolds AJ et al (2001) Transspecies hair growth induction by human hair follicle dermal papillae. Exp Dermatol 10:229–237 27. Jave-Suarez L F, Langbein L, Winter H et al (2004) Androgen regulation of the human hair follicle: the type 1 hair keratin hHa7 is a direct target gene in trichocytes. J Invest Dermatol 122:555–564 28. Kaufman KD, Olsen EA, Whiting D et al (1988) Finasteride in the treatment of men with androgenetic alopecia. J Am Acad Dermatol 39:578–589 29. Kligman AG (1959) The human hair cycle. J Invest Dermatol 33:307–316

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Chapter 3

Neuroimmunology of the Hair Follicle Eva M. J. Peters, Vladimir A. Botchkarev

 

 

3

6

Synonyms neu­roimmune mediation, neurobiology, psycho­ neuroimmunology



Key Features

• Neural networks in contact with immune cells are dense around the hair follicle. • The hair follicle produces and consumes neuroimmune mediators. • Neural and immune networks and mediators fluctu-

• Neuroimmune interaction and mediators affect hair •

ate throughout the hair cycle.

growth and disorders: they are turned on by environmental factors such as stress. Interference with neuroimmune action is a pharmacological target in hair disease management.

 

Contents 3.1 3.2 3.3 3.4 3.5 3.6

3.1

Introduction  . . . . . . . . . . . . . . . . . . . . . . . . . .   41 History  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   42 Neuro–Immuno–Epithelial Interactions in Normal and Pathological Hair Growth  .   42 Structure and Function of HF Innervation    43 Neuroimmune Regulatory Network Around Normal HFs  . . . . . . . . . . . . . . . . . . .   44 Neuroimmune Interactions in StressMediated Hair Growth Inhibition  . . . . . . . .   45

Introduction

Despite its tiny size, the hair follicle (HF) is a complex organ that can regulate its cyclic growth and regression processes in a largely autonomous fashion through close communication between its epithelial and mesenchymal components [9, 47]. Hair research and pharmacologic intervention therefore focus mainly on local regulatory circuits, such as HF testosterone metabolism or growthfactor-activated pathways [16, 46]. Beyond its autono-

3.7 3.8 3.9 3.10

Neuroimmunological Interactions in Autoimmune Hair Loss  . . . . . . . . . . . . . . Experimental Techniques  . . . . . . . . . . . . . . . Clinical Relevance  . . . . . . . . . . . . . . . . . . . . . Outlook – Future Developments  . . . . . . . . . Summary for the Clinician  . . . . . . . . . . . . . .

  46   47   47   48   48

References   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   48

mous regulation of growth and regression however, the HF is located in an environment rich in structures and cells that connect local to systemic regulatory systems, such as the endocrine (Chap.  2) and the nervous and immune systems (Fig. 3.1) [20, 34, 39, 40]. Interaction of these systems with the HF and with each other leads to a strong impact on hair growth behavior. Neuronal mediators such as the sensory neuropeptide substance P (SP), for example, can turn on or terminate hair growth control mechanisms, such as keratinocyte proliferation or neurogenic inflammation

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3.2

3

Fig.  3.1  The hair follicle is a target for systemic regulatory mechanisms involving the immune and nervous systems. This schematic figure depicts the hair follicle as an exemplary neuro­immune–mesenchymal–epithelial interaction system at the point between challenges and adaptive mechanisms

associated with HF regression [35, 39, 40]. At the same time, growth factors excreted by HF cells, such as the neurotrophin nerve growth factor (NGF), modulate the structure and function of their environment through, for example, perifollicular innervation, intra- and perifollicular immune cell populations, and neuroimmune communication [13, 37, 43]. In short, the HF and its local regulatory circuits depend on systemic mechanisms that can override local hair growth regulation and therefore they deserve close scrutiny, scientific appreciation, and pharmacologic targeting. Throughout this chapter we will focus on the HF as a model organ defined by lifelong plasticity of the accompanying immune cell populations and perifollicular innervation. This model may serve as an instructive blue-print for the analysis and understanding of neuro­ immune regulation in epithelial tissue remodeling processes.

History

Our knowledge of the HF as a target for cutaneous nerve fibers and immune cells reaches back to the time when techniques to detect nerve fibers and immune cells in situ became available a century ago. Modern research approaches, in particular the development of transgenic mouse models and great advances in immunohistochemistry and molecular biology, have helped in the identification of a large array of candidates responsible for mediating pilo–neural–immuno interactions [14, 31, 39]. However, William Montagna’s statement in his famous book The Structure and Function of Skin more than 30 years ago still holds true today: “The largest sense organ of the body, interposed between the organism and its environment, skin must maintain that organism in a constant state of awareness of all environmental changes. ... Yet precious few of the problems that involve cutaneous innervation and specific cutaneous sensibilities have been solved, let alone the clinical problems that are in some way related to the peripheral nervous system.” Since the early 1990s, however, interdisciplinary research focusing on the nervous system and its interaction with the immune system has been constantly producing new perspectives and insights into neuroimmune regulatory mechanisms in healthy and diseased skin, many of which apply to hair growth.

3.3

Neuro–Immuno–Epithelial Interactions in Normal and Pathological Hair Growth

The HF is a densely innervated skin appendage, and relationships between the HF and its innervation are truly bi-directional: while neuromediators and neuropeptides are capable of influencing hair growth, HF keratinocytes produce NGF and other neurotrophic factors and induce remodeling of skin innervation in a hair-cycledependent manner [13]. The same is true for interactions between the HF and immune cells located nearby in the dermis and subcutaneous tissue. Keratinocytes in “healthy” HFs for example are protected from an attack by immune cells by their “immune privilege” characterized by low levels of major histocompatibility complex (MHC) class I/II antigens [33]. Below, we briefly summarize our current knowledge on the neuro–immuno– epithelial interactions during the normal hair cycle, as well as in a number of pathological skin conditions, such as the stress response and autoimmune hair loss [alopecia areata (AA)].

Neuroimmunology of the Hair Follicle

Chapter 3

Nerve fibers that innervate HFs form two distinct neural networks: the first is located around the neck of the HF just underneath the epidermis and contains sensory C fibers along with sympathetic fibers, while the second is located around the permanent midsection of the HF between the isthmus of the sebaceous gland and the insertion of the arrector pili muscle into the HF and contains longitudinal Aδ fibers and circular C fibers (Fig.  3.2) [31, 39]. This latter localization is especially intriguing since it is near the HF stem cell region [16]. Both

networks contain sensory nerve fibers, e.g., expressing calcitonin-gene related peptide (CGRP), and autonomic nerves expressing choline acetyl transferase (ChAT) [12, 35, 36]. Close by, the arrector pili muscle inserts into the hair follicle epithelium and nerve fiber bundles that give rise to additional noradrenergic and peptidergic nerve fibers innervating the muscle are regularly found nearby (Fig. 3.3). In mice, the number of perifollicular nerves fluctuates very significantly during the hair cycle, increasing during early anagen and later decreasing during late anagen–catagen [11, 12, 35]. Substance P and the β2-adrenoreceptor agonist isoproterenol accelerate anagen progression in murine skin organ culture, whereas

Fig.  3.2  The hair follicle is the target for systemic neuroimmune regulatory circuits. Hair follicles are densely innervated and their innervation keeps close contacts with immunocytes

affecting the hair cycle, as described throughout the chapter. Please note the dramatic remodelling within the hair follicle compartment accompanied by neuronal plasticity

3.4

Structure and Function of HF Innervation

43

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3

Fig.  3.3  Substance-P-immunoreactive nerve fibers and mast cell contacts during the murine hair cycle. Substance-P-immunoreactive (IR rhodamine immunofluorescence) nerve fibers are located in nerve fiber bundles at the border between the dermis (d) and subcutis (sc) region (large arrows) close to the bulge region of the hair follicle, where the arrector pili muscle (apm, not labelled, therefore only visible as background label

and lined up nuclei) inserts (iapm) below the sebaceous gland (sg). Note the close contact between a single fiber and a mast cell (fluorescein fluorescence) in anagen skin. Cell nuclei are counterstained with DAPI. Note the dermal papilla (dp) at the dermis–subcutis border and the autofluorescence of the hair shaft (hs) in telogen and the missing hair shaft in the empty hair channel (hc) in early anagen

CGRP inhibits anagen promotion by SP [12, 35]. In turn, HF keratinocytes produce neurotrophins that influence perifollicular nerve fibers, inducing hair-cycledependent remodeling [13, 43]. In particular, during anagen HF keratinocytes produce predominantly NGF, while during catagen production of other neurotrophins [brain-derived neurotrophic factor (BDNF), neurotrophins-3 and -4 (NT-3, NT-4)] increases [13, 43]. Besides their effects on skin nerves, neurotrophins also influence hair cycle progression: NGF has stimulatory effects on anagen development, while all neurotrophins promote anagen–catagen transition and catagen progression, at least in part via binding to the p75 kD neurotrophin re-

ceptor (p75NTR), implicated in keratinocyte apoptosis [13, 37, 43].

3.5

Neuroimmune Regulatory Network Around Normal HFs

The epithelium of normal HFs is characterized by a relative immune privilege and expresses very low levels of MHC class I/II antigens accompanied by the local production of potent immunosuppressants [e.g., transforming growth factor-beta1 (TGFβ1) and alpha-

Neuroimmunology of the Hair Follicle

Chapter 3

melanocyte-stimulating hormone (α-MSH)] [32, 33]. However, perifollicular nerve fibers that travel through the subepidermal and interfollicular dermis are located close to immune cells (macrophages, dendritic cells, mast cells) [40]. There is increasing evidence to suggest that neuroimmune interactions play an important role in the control of HF cycling (Fig. 3.4) [39]. Most often, skin nerve fibers form close contacts with mast cells [10, 38]. Peptidergic nerve fibers can communicate with mast cells through the release of neuronal mediators such as SP, CGRP, α-MSH, corticotrophin-releasing hormone (CRH), and many more [40]. Interestingly, these interactions also show hair-cycle-dependent changes, thus implicating the involvement of cross-talk between mast cells and nerves in hair growth regulation. Indeed, mast cell mediators are capable of stimulating anagen onset and progression, as well as promoting catagen [25, 26, 30]. In addition to mast cells, nerve fibers close to the HF contact dendritic cells. Here they may play an impor-

tant role in the processing of antigen presentation [40]. Substance P, for example, can activate antigen presentation, while CGRP potently inhibits it. This last observation may explain why contact hypersensitivity is difficult to induce in mice that have all their HFs in the growth phase of the hair cycle, namely anagen. During this phase, CGRP-positive nerve fibers are present in high numbers in the murine back skin [35], facilitating contacts with Langerhans and other antigen-presenting cells.

Fig. 3.4  The “neuroimmune–hair follicle axis”. This schematic drawing summarizes neuroimmune interaction and its impact on hair-growth regulation as an example of the interdependence of growth factor signals on neurogenic inflammatory signals and specific immune responses. (ACTH Adrenocor-

ticotropic hormone, α-MSH alpha melanocyte stimulating hormone, CRH corticotrophin-releasing hormone, NGF nerve growth factor, PAR proteinase-activated receptor, SP substance P, TNF-α tumor necrosis factor alpha)

3.6

Neuroimmune Interactions in Stress-Mediated Hair Growth Inhibition

In general, neuropeptide release from nerve fibers is considered to be pro-inflammatory and results in mast cell degranulation and the release of a multitude of

45

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pro-inflammatory mediators, such as histamine, into interfollicular tissue [6, 7, 40]. Mast cell release of histamine, proteases and additional neuropeptides initiates neurogenic inflammation, a defense mechanism created to provide fast host defense against microbial and parasitic intruders [6]. Subsequent inflammatory cascades involving cytokines released by mast cells or triggered by mast cell secretagogues produce a more specific immune response [40]. This inflammatory cascade headed by SP and NGF is dependent on neuroimmune interaction and has lately been implicated as a prominent aggravating factor in the premature termination of hair growth induced by environmental stressors such as noise (Fig. 3.4) [5, 37]. It has been shown that upon acute stress exposure NGF is released into the blood, e.g., from submaxillary glands of male mice [1] and perhaps other sources, making it a likely mediator of stress. The role of NGF as a local stress-response mediator involved in neurogenic inflammation was also recently established in a mouse model for perceived psycho-emotional stress [37]. In this model, a stress-induced increase in the numbers of apoptotic cells in the HF can be antagonized by NGF neutralization [37], demonstrating an important role for NGF in stress-induced HF damage. Remarkably, serving this role, NGF triggers complex skin and HF responses to stress [37]. On the one hand, NGF can promote the outgrowth of SP-positive nerve fibers, e.g., towards mast cells, thereby building up a network that allows for increased neurogenic inflammatory responses upon exposure to stress [20, 43]. On the other hand, NGF can stimulate mast cell degranulation and the release of proinflammatory cytokines by itself [24]. Although the roles for Trk and p75NTR in the control of this very complex pathobiological response remain to be elucidated, these data suggest that both Trk and p75NTR antagonists may be used for preventing stress-induced skin and hairgrowth abnormalities.

3.7

Neuroimmunological Interactions in Autoimmune Hair Loss

Alopecia areata (AA) is an autoimmune disorder of the HF characterized by intra- and perifollicular inflammatory cell infiltrates consisting of CD4+ and CD8+ T-lymphocytes, macrophages, and Langerhans cells that target follicular keratinocytes, melanocytes, and dermal papilla fibroblasts [23, 27, 28, 33, 44]. Aberrant expression of human leukocyte antigen (HLA) classes I and II occurs in keratinocytes of the hair bulb, leading to the autoimmune attack by CD8+ T-lymphocytes, followed by the development of inflammatory cell infiltration in and around the HFs [17, 18, 21].

 

Human HFs affected by AA are innervated by SPimmunoreactive nerve fibers, which may modulate the perifollicular immune response [22, 23]. Interestingly in this context, a link between AA and stress has been described in humans [19, 29]. To better understand the role of SP as an immunomodulatory neuropeptide in AA, we studied its expression and effects on immune cells in the C3H/HeJ mouse model of AA [45]. Our data reveal that the number of nerve fibers containing SP strongly depends on the disease stage: during the early phase of AA development, the number of SP-immunoreactive nerve fibers in skin increased, compared to non-affected mice [45]. However, during the advanced stage of AA, the number of SP-immunoreactive nerves and SP protein levels in skin decreased, whereas the expression of the SP-degrading enzyme neutral endopeptidase increased, compared to control skin [45]. In AA, the SP-binding neurokinin-1 receptor (NK-1) is expressed on CD8+ lymphocytes and macrophages accumulating around affected HFs. Additional SP supply to the skin of AA-affected mice leads to a significant increase of mast cell degranulation and to accelerated HF regression (catagen), accompanied by an increase of CD8+ cells expressing granzyme B. These data suggest that SP, neutral endopeptidase and NK-1 receptor serve as important regulators in the molecular signaling network modulating the inflammatory response in auto­immune hair loss. Numerous indications suggest that neurotrophins also play an important role in the pathogenesis of auto­ immune diseases [2, 3]. We have recently shown that in the C3H/HeJ mouse model for AA steady-state levels of NGF, BDNF, NT-3 and NT-4 proteins determined by enzyme-linked immunosorbent assay (ELISA) remain similar to that seen in control unaffected skin [8]. These data are consistent with previous reports showing high levels of neurotrophins in other autoimmune disorders [2, 3]. In C3H mouse back skin, anagen HFs not affected by AA showed moderate expression of NGF, the absence of BDNF and co-expression of Trk and p75NTR in the outer root sheath. In the AA-affected anagen HFs, the levels of NGF and BDNF were elevated in the outer and inner root sheaths, respectively, and all Trk receptors were downregulated in the outer root sheath. In contrast, the apoptotic receptor p75NTR was upregulated in the outer root sheath and was ectopically expressed in the dermal papilla. We also showed that neurotrophins were strongly expressed in macrophages in inflammatory cell infiltrates around the HFs. In the AA-affected skin, CD4+ cells expressed TrkB and TrkC. In the inflammatory infiltrates, numerous macrophages identified by MOMA-2 immunoreactivity co-expressed TrkB, while dermal dendritic NLDC145-immunoreactive cells were also p75NTRpositive. Double immunolabeling showed that CD8+

Neuroimmunology of the Hair Follicle

cells in the inflammatory infiltrates also expressed p75NTR, implicating the involvement of neurotrophins in the control of apoptosis in CD8+ lymphocytes [8]. While the significance of these observations remains to be further determined, they support the general idea that neurotrophins may modulate AA development by targeting cutaneous nerves, immune cells, and HF keratinocytes.

3.8

Experimental Techniques

Neuroimmunology of the HF is best studied in animal models, since the detection, display and, most importantly, the statistical analysis of data from nerve fibers and neuronal mediators in concert with immune cells all require the analysis of complex tissue interactions and special acquisition techniques [42]. The respective signaling molecules are small and rapidly digested after tissue dissection, demanding pericardial perfusion with a fixative such as paraformaldehyde for optimal detection. The animal model also allows us to follow neuronal plasticity through analysis of defined time points during an experimental setting [42], a task difficult to achieve in humans. In the animal model it is possible to eliminate or enhance specific neuroimmune interaction pathways or signaling cascades to probe their functional relevance and possible therapeutic value. Neurotrophins, for example, can be knocked out or overexpressed transgenically [13]. Experiments along this line led to the pathophysiological insights into hair cycle control discussed above. Other models involve established hair disease models such as that for AA. In this model SP has been shown to play an initiating role in the inflammatory cascade leading to selective inflammatory destruction of anagen HFs (see above). Surgical or pharmacological denervation or inhibition of neuronal mediator signaling has also been proven as a useful measure to analyze the impact of neuroimmune interactions on hair growth. In denervated skin for example hair growth appears to terminate, while increased hair growth could be observed in hyperinnervated skin, demonstrating the dependence of hair growth regulation on growth factors derived from nerve fibers [31, 39]. Furthermore, organ culture experi­ments employing denervated skin exposed to selective neuropeptides demonstrate that SP acts as a hair growth stimulator through direct growth factor capacities [31, 39]. This latter organ culture experiment demonstrates that the study of neuroimmune interactions and their effect on hair growth in vitro is suitable for evaluating the direct actions of neuroimmune mediators on hair growth. However, it is at the same time limited to the

Chapter 3

analysis of individual HF cell populations and their response, but does not supply insight into the net effect of local and additional systemic signaling by the respective molecules. For example, culture models have shown that, like SP, CGRP and vasoactive intestinal peptide (VIP) can also promote keratinocyte proliferation in mice and humans [31, 38]. Neurotransmitters such as noradrenaline (norepinephrine) and neurotrophins have also been shown to promote keratinocyte proliferation in culture. However, in vivo hair growth experiments show that neuropeptides and neurotrophins do not necessarily enhance hair growth through their promotion of keratinocyte proliferation [8, 13, 31]. Indeed, they may have quite the opposite effect, either by interacting with receptors that aren’t necessarily expressed on cultured cells but are found in crucial locations on the growing HF, or through the induction of deleterious perifollicular inflammation, which then overrides any direct growth-promoting effects on HF cells. On occasion the analysis of cell-to-cell interactions may also be elucidating for hair research and the pharmacological targeting of hair growth mechanisms. Nerve fibers for example can be co-cultivated with mast cells, and experiments have shown that mast cell degranulation is positively enhanced in the presence of SP-positive nerve fibers [48].

3.9

Clinical Relevance

Most of our knowledge on the neuroimmune regulation of hair growth has been gained in experiments using animal models, especially when it comes to pharmacologic or other therapeutic interventions. In the mouse, NK-1 antagonists, NGF-neutralizing antibodies and surprisingly minoxidil [4, 5, 37] are all capable of counteracting stress-induced deleterious neurogenic inflammation. NK-1 antagonists and minoxidil thereby appear to be especially promising compounds to be used in the pharmacotherapy of hair loss associated with neurogenic inflammation, since they have long been approved as therapeutic agents in humans. However, if results like those obtained in animal models can be reproduced in humans, they remain speculative despite promising in vitro data [39, 41]. Our knowledge to date therefore primarily serves to inform and enlighten patients with unwanted hair loss, especially under stress and in the inflammatory context – patients who are often frustrated by the narrow treatment options available to them and the small number of medical personnel who can provide expert knowledge. It remains a challenging research task for future efforts to prove the effectiveness of pharmaceuticals that target neuroimmune interactions and to test further target compounds, such as specific CGRP-

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receptor antagonists, mast cell stabilizers and the depletion of nerve fibers, e.g., by capsaicin.

  2.

3.

3

3.10

Outlook – Future Developments

We have learned of many of the neuroimmune interaction pathways that affect hair growth; however, this research has resulted in few clinical approaches to master unwanted hair loss, for example. This means that further research and testing of highly specific neurotransmitter, neuropeptide and neurotrophin agonists and antagonists are required. Minoxidil, for example, is one of the few hair growth remedies on the market, although we understand little about its function. One relevant mechanism through which it may be effective is the inhibition of neurogenic inflammation, as has been shown in the mouse model [4, 39]. However, clinical follow-up studies to confirm this effect in the human have yet to be performed.

4.

5.

6. 7.

8.

9.

Summary for the Clinician The hair follicle (HF) is densely innervated and possesses a unique array of immune cell populations. This provides each HF with neuroimmune interaction pathways that adapt local hair-growth regulatory pathways to systemic requirements, for example in temperature regulation or protection from injury. It also explains why the HF so often acts as a messenger for systemic disease. Denser hair growth, for example, can be expected after neuronal activation through injury, while stimulation of neurogenic inflammation, for example through stress, can terminate hair growth. Knowledge of these interaction pathways does not yet provide us with many clinically approved treatment options, however imparting careful and sound information gives great relief to many patients, who have difficulty in understanding their hair loss and are frightened that they have lost their hair for ever.

10.

11.

12.

13.

14.

15. 16.

R eferences 1.

Alleva E, Petruzzi S, Cirulli F et al (1996) NGF regulatory role in stress and coping of rodents and humans. Pharmacol Biochem Behav 54(1):65–72

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Aloe L, Skaper SD, Leon A et al (1994) Nerve growth factor and autoimmune diseases. Autoimmunity 19:141–150 Aloe L, Simone MD, Properzi F (1999) Nerve growth factor: a neurotrophin with activity on cells of the immune system. Microsc Res Techn 45:285–291 Arck P, Handjiski B, Peters EMJ et al (2003) Topical minoxidil counteracts stress-induced hair growth inhibition in mice. Exp Dermatol 12[5]:580–590 Arck PC, Handjiski B, Peters EM et al (2003) Stress inhibits hair growth in mice by induction of premature catagen development and deleterious perifollicular inflammatory events via neuropeptide substance P-dependent pathways. Am J Pathol 162:803–814 Baluk P (1997) Neurogenic inflammation in skin and airways. J Investig Dermatol Symp Proc 2:76–81 Black PH (2002) Stress and the inflammatory response: a review of neurogenic inflammation. Brain Behav Immun 16:622–653 Botchkarev VA (2003) Neurotrophins and their role in pathogenesis of alopecia areata. J Investig Dermatol Symp Proc 8:195–198 Botchkarev VA, Kishimoto J (2003) Molecular control of epithelial-mesenchymal interactions during hair follicle cycling. J Invest Dermatol Symp Proc 8:46–55 Botchkarev VA, Eichmüller S, Maurer M et al (1995) A simple immunofluorescence-technique for co-visualizing mast cells and peptidergic nerve fibers in skin. J Invest Dermatol 105:718 Botchkarev VA, Eichmüller S, Johansson O et al (1997) Hair cycle-dependent plasticity of skin and hair follicle innervation in normal murine skin. J Comp Neurol 386:379–395 Botchkarev VA, Peters EM, Botchkareva NV et al (1999) Hair cycle-dependent changes in adrenergic skin innervation, and hair growth modulation by adrenergic drugs. J Investig Dermatol 113:878–887 Botchkarev VA, Botchkareva NV, Peters EM et al (2004) Epithelial growth control by neurotrophins: leads and lessons from the hair follicle. Prog Brain Res 146:493–513 Christoph T, Muller-Rover S, Audring H et al (2000) The human hair follicle immune system: cellular composition and immune privilege. Br J Dermatol 142:862–873 Cotsarelis G (2006) Epithelial stem cells: a folliculocentric view. J Investig Dermatol 126:1459–1468 Cotsarelis G, Millar SE (2001) Towards a molecular understanding of hair loss and its treatment. Trends Mol Med 7:293–301 Gilhar A, Ullmann Y, Berkutzki T et al (1998) Autoimmune hair loss [alopecia areata] transferred by T lymphocytes to human scalp explants on SCID mice. J Clin Invest 101:62–67

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Gilhar A, Shalaginov R, Assy B et al (1999) Alopecia areata is a T-lymphocyte mediated autoimmune disease: lesional human T-lymphocytes transfer alopecia areata to human skin grafts on SCID mice. J Invest Dermatol Symp Proc 4:207–210 Gupta MA, Gupta AK, Watteel GN (1997) Stress and alopecia areata: a psychodermatologic study. Acta Derm Venereol 77:296–298 Hendrix S, Peters EMJ (2007) Neuronal plasticity and neuroregeneration in the skin: the role of inflammation. J Neuroimmunol 184(1-2):113–126 Hoffmann R (1999) The potential role of cytokines and T cells in alopecia areata. J Investig Dermatol Symp Proc 4:235–238 Hordinsky MK, Ericson ME (1996) Relationship between follicular nerve supply and alopecia. Dermatol Clin 14:651–660 Hordinsky M, Ericson M (2004) Autoimmunity: alopecia areata. J Investig Dematol Symp Proc 9:73–78 Marshall JS, Gomi K, Blennerhassett MG et al (1999) Nerve growth factor modifies the expression of inflammatory cytokines by mast cells via a prostanoid-dependent mechanism. J Immunol 162:4271–4276 Maurer M, Paus R, Czarnetzki BM (1995) Mast cells as modulators of hair follicle cycling. Exp Dermatol 4:266–271 Maurer M, Fischer E, Handjiski B et al (1997) Activated skin mast cells are involved in murine hair follicle regression [catagen]. Lab Invest J Technical Methods Pathol 77:319–332 McDonagh AJ, Messenger AG (2001) Alopecia areata. Clin Dermatol 19:141–147 McElwee KJ, Freyschmidt-Paul P, Sundberg JP et al (2003) The pathogenesis of alopecia areata in rodent models. J Investig Dermatol Symp Proc 8:6–11 Misery L, Rousset H (2001) Is alopecia areata a psychosomatic disease? Rev Med Intern 22:274–279 Paus R, Maurer M, Slominski A et al (1994) Mast cell involvement in murine hair growth. Dev Biol 163:230–240 Paus R, Peters EM, Eichmüller S et al (1997) Neural mechanisms of hair growth control. J Investig Dermatol Symp Proc 2:61–68 Paus R, Christoph T, Müller_Röver S (1999) Immunology of the hair follicle: a short journey into terra incognita. J Investig Dermatol Symp Proc 4:226–234 Paus R, Nickoloff BJ, Ito T (2005) A “hairy” privilege. Trends Immunol 26:32–40 Paus R, Theoharides TC, Arck PC (2006) Neuroimmunoendocrine circuitry of the “brain-skin connection”. Trends Immunol 27:32–39

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Peters EM, Botchkarev VA, Botchkareva NV et al (2001) Hair-cycle-associated remodeling of the peptidergic innervation of murine skin, and hair growth modulation by neuropeptides. J Investig Dermatol 116:236–245 Peters EMJ, Botchkarev VA, Müller-Röver S et al (2002) Developmental timing of hair follicle and dorsal skin innervation in mice. J Comp Neurol 448[1]:28–52 Peters EMJ, Handjiski B, Kuhlmei A et al (2004) Neurogenic inflammation in stress-induced termination of murine hair growth is promoted by nerve growth factor. Am J Pathol 165[1]:259–271 Peters EMJ, Kuhlmei A, Tobin DJ et al (2005) Stress exposure modulates peptidergic innervation and degranulates mast cells in murine skin. Brain Behav Immun 19[3]:252–262 Peters EMJ, Arck PC, Paus R (2006) Hair growth inhibition by psychoemotional stress: a mouse model for neural mechanisms in hair growth control. Exp Dermatol 15[1]:1–16 Peters EM, Ericson ME, Hosoi J et al (2006) Neuropeptide control mechanisms in cutaneous biology: physio­ logical and clinical significance. J Investig Dermatol 126:1937–1947 Peters EMJ, Liotiri S, Bodó E et al (2007) The brain-skin axis involves the human hair follicle: the stress mediator Substance P stimulates degranulation of connective tissue sheath mast cells and brakes the immune privilege. Am J Pathol (in press) Peters EMJ, Peker B, Hendrix S (2007) Skin and hair follicle innervation in experimental models: a review and guide for the evaluation of neuronal plasticity in the back skin of mice. Nat Meth (submitted) Peters EMJ, Raap U, Welker P, Tanaka A et al (2007) Neurotrophins act as neuroendocrine regulators of skin homeostasis in health and disease. Horm Metab Res (in press) Shapiro J, Madani S (1999) Alopecia areata: diagnosis and management. Int J Dermatol 38 [Suppl 1]:19–24 Siebenhaar, F, Sharov AA, Peters EMJ et al (2007) Substance P as immunomodulatory neuropeptide in a mouse model autoimmune hair loss [alopecia areata]. J Invest Dermatol (in press) Stenn KS, Cotsarelis G (2005) Bioengineering the hair follicle: fringe benefits of stem cell technology. Curr Opin Biotechnol. 16:493-7 Stenn KS, Paus R (2001) Controls of hair follicle cycling. Physiol Rev 81:449–494 Suzuki R, Furuno T, McKay DM, Wolvers D (1999) Direct neurite-mast cell communication in vitro occurs via the neuropeptide substance P. J Immunol 163:2410–2415

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Chapter 4

Biology of Hair Follicle Pigmentation Desmond J. Tobin

 

 

4

6

Synonyms hair color, melanin production, melanogenesis



Key Features

• The hair follicle and epidermal pigmentary units are

broadly distinct and can be distinguished principally on the basis of the former’s stringent coupling to the hair growth cycle compared to the latter’s continuous melanogenesis. Melanin synthesis and its transfer from melanocyte to hair bulb keratinocytes both depend on the availability of melanin precursors and are regulated by cutaneous signal transduction pathways that: (1) are both dependent and independent of receptors, (2) act through auto-, para- or intracrine mechanisms, and (3) can be modified by hormonal signals. Follicular melanocytes appear to be more sensitive than epidermal melanocytes to aging influences, as indicated by dramatic hair graying/canities. This is likely to reflect differences in the epidermal and follicular microenvironments.

•

•

• Skin and hair color contribute significantly to our • •

overall visual appearance and to social/sexual communication; thus disorders of follicular pigmentation may cause psychological trauma. Hair pigment may also contribute to rapid excretion of heavy metals, chemicals, and toxins from the body by their selective binding to melanin. The availability of cell culture methodology for isolated hair follicle melanocytes and for intact anagen hair follicle organ culture, as well as improved technologies for follicular delivery in vivo should provide important research tools for elucidating the regulatory mechanisms of hair follicle pigmentation.

 

Contents 4.1 4.2 4.3 4.3.1 4.3.2 4.3.3 4.3.4 4.3.5 4.3.5.1

Introduction   . . . . . . . . . . . . . . . . . . . . . . . . . History  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Structure and Function/Pathophysiology/ Developments   . . . . . . . . . . . . . . . . . . . . . . . . Origin and Development of the Hair Follicle Pigmentary Unit  . . . . . . . . . . . . . . . . Comparative Biology of Epidermal and Hair Follicle Melanocytes   . . . . . . . . . . The Fate of Hair Follicle Melanocytes During the Hair Growth Cycle  . . . . . . . . . . Regulation of Pigmentation in the Hair Follicle  . . . . . . . . . . . . . . . . . . . . . Aging of the Follicle Melanocytes and Hair Graying (Canities)  . . . . . . . . . . . . . Histopathology of Canities   . . . . . . . . . . . . .

  52   53   53   53   54   55   60   61   62

4.3.5.2 4.3.5.3 4.4 4.4.1 4.4.1.1 4.4.1.2 4.4.1.3 4.4.1.4 4.5 4.5.1 4.5.2

Impact of Melanocyte Loss on the Hair Follicle  . . . . . . . . . . . . . . . . . . . . Spontaneous Re-Pigmentation of Hair in Canities  . . . . . . . . . . . . . . . . . . . . . Clinical Relevance of Hair Pigmentation   Disorders Affecting the Hair Follicle Pigmentary Unit  . . . . . . . . . . . . . . . . . . . . . . Alopecia Areata  . . . . . . . . . . . . . . . . . . . . . . . Vitiligo  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Circumscribed Poliosis  . . . . . . . . . . . . . . . . . Genetic Poliosis  . . . . . . . . . . . . . . . . . . . . . . . Experimental Techniques  . . . . . . . . . . . . . . . Hair Follicle Melanocyte Culture  . . . . . . . . Whole-Organ Hair follicle Ex Vivo Culture  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

  64   64   64   66   66   66   66   67   67   67   67

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Desmond J. Tobin 4.5.3 4.6 4.6.1

4

4.1

Delivery of Agents to the Hair Follicle  . . . .   69 Outlook – Future Developments  . . . . . . . . .   69 Is Canities Reversible?  . . . . . . . . . . . . . . . . .   69

Introduction

As social beings we communicate significantly via our physical appearance. Skin and hair color contribute disproportionately to this overall visual demeanor. The main contributor to this phenotypic palette is a class of mixed indole-rich compounds called melanins formed within unique cytoplasmic organelles called melanosomes produced within the melanocyte via a complex, phylogenetically ancient, biochemical pathway called melanogenesis. While hair growth and pigmentation facilitated evolutionary success in non-human mammals (i.e., via thermal insulation, camouflage, social and sexual communication, and sensory perception) these traits do not appear to have been critical for survival in humans. Why humans should be unique among primates in exhibiting pigmented scalp hair that is very thick, long, and pigmented remains unclear, but it is likely to reflect particular evolutionary selective pressures present during the early stages of human evolution. One possible explanation may pertain to human evolution by seacoasts and riverbanks where fish was a dominant part of our early diet. As many fish species concentrate heavy metals it would have been important to develop strategies to prevent the build-up of toxic metals. This could be readily achieved by their selective binding to melanin in a rapidly growing and melanized tissue. The hair follicle is a highly proliferative tissue in which melaninaccepting bulbar keratinocytes form the pigmented hair shaft. In this way the trapping of toxins (including heavy metals) within long, deeply melanized, scalp hair fibers would limit their access to the living tissue of the highly vascularized scalp. Furthermore, our relative nakedness draws much attention to our facial and scalp hair. These modifications may have been critical for the development of optimal communication strategies. Deep brown-black hair is the norm for over 90% of the world’s human population. Indeed, it may appear somewhat paradoxical that black scalp hair also predominates in primates (including humans) living in tropical climes, where the thermal insulating properties of melanin (via trapping of radiant heat) appears to be misplaced. A possible explanation may be protection against sunstroke afforded by deep skin and hair pigmentation, as well as the contribution of melanin’s very efficient and fast exchange of ion transport and efflux to adequate salt balance [88]. So what about the remaining

  Summary for the Clinician  . . . . . . . . . . . . . .   71

References   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   71

5%–10% of the world’s population (mostly originating in northern Europe) who have emerged with a bewildering array of hair colors that range from white blonde, yellow blonde, auburn to red and all shades in between? Recent advances in molecular genetics have started to yield clues to explain the basis of this dramatic diversity of human cutaneous pigmentation whereby these phenotypes appear to be linked to the degree of variability (i.e., polymorphism) in the melanocortin-1 receptor (MC1R) gene [51]. This receptor is activated through binding of the pro-melanogenic peptides α-melanocyte stimulating hormone (α-MSH) and adrenocorticotropin hormone (ACTH). For example, most northern Europeans with red hair are homozygotes or compound heterozygotes for a limited number of MC1R mutations [50]. Natural selection pressures may have restrained mutation of this gene in the hot, humid and sunny tropics, thereby ensuring dark hair and skin. These pressures may have been less critical as humans migrated from Africa to less sunny, less humid, colder northern climes, such that the “brake” on gene mutation was lifted, resulting in the emergence of functionally relevant mutations in the MC1R gene. Indeed, more recent data suggest that variations in the MC1R are common in non-African populations [51]. Sadly, regardless of our original natural hair color, the follicular melanin unit appears to have an intrinsic “biologic clock,” and canities is the inevitable harbinger of disappearing youth. This chapter aims to discuss our current thinking on several aspects of follicular pigmentation biology in humans. Much of this knowledge derives from the intensive study of murine coat color. This species exhibits a high level of coat color mutations, and correlates of these continue to be discovered in humans. There is a caveat here as recent research highlights several differences in the regulation of melanogenesis between mice and humans. I will begin with an assessment of how the follicular pigmentary unit is structurally configured during development, before focusing on the hair-cyclespecific influences on the follicular melanocytes that do not impact on melanocytes in the epidermis. This will be followed by close examination of the regulation of melanin synthesis and its transfer from melanocyte to hair bulb keratinocytes, which involves cutaneous signal transduction pathways that are both dependent and independent of receptors, that act through auto-, para- or intracrine mechanisms, and that can be modified by hormonal signals. From there we will examine our current understanding of the mechanisms underlying follicular

Biology of Hair Follicle Pigmentation

melanocyte aging that result in hair graying/canities, as well as the pathologic basis of selected hair pigmentation disorders [80], before concluding with a brief assessment of how new experimental techniques may facilitate further advances in hair pigmentation sciences. A glossary of key terms is provided in Table 4.1, page 70.

Chapter 4

an exceptional report by Fitzpatrick, Brunet and Kukita [18] in 1958 entitled The nature of hair pigment, which featured prominently in Montagna and Ellis’ seminal book The Biology of Hair Growth.

4.3 4.2

History

It was not until the seventeenth century that a scientific approach to the study of pigmentation was reported by Italian anatomist Malphigi. From then, fast forward to 1950s USA where the rigors of cellular and molecular analyses were applied to the study of pigmentation of the epidermis. Pivotal descriptions of the “epidermal melanin unit” and the dissection of elements of the melanin biosynthetic pathway (melanogenesis) followed in the 1950s by Fitzpatrick and Breathnach [17], and by Lerner and Fitzpatrick [37]. The study of follicular pigmentation in particular was significantly advanced by

53

4.3.1

Structure and Function/ Pathophysiology/Developments Origin and Development of the Hair Follicle Pigmentary Unit

Melanocytes of both the epidermal melanin unit and the follicular pigmentary unit derive from melanoblasts that migrate from the neural crest to the skin. Commitment and differentiation of cells of the melanocytic lineage in the neural crest are determined by several factors including, amongst others, microphthalmia-associated transcription factor (MITF), SOX10, Pax3, KIT, fibroblast growth factor-2, and endothelin 3 (Fig. 4.1) [15]. Melanoblasts migrate out of the neural crest along ste-

Fig. 4.1  a Melanocyte development. Melanocytes migrate from the neural crest to the skin and hair follicle along stereotyped routes and are spatiotemporally influenced by a range of developmental and differentiation cues. [BCL-2 B-cell CLL/ lymphoma 2, bFGF basic fibroblast growth factor, ECM extracellular matrix, EDNRB endothelin B receptor, ET-3 endothelin-3, HGF hepatocyte growth factor, KIT stem cell factor receptor, LIF leukemia inhibitory factor, Met HGF receptor, MITF microphthalmia-associated transcription factor, Pax3 paired box gene 3, PDGF(R) platelet-derived growth factor (receptor), POMC pro-opiomelanocortin, SCF stem cell factor, SOX10 SRY-box containing gene 10.] Adapted from Tobin & Bystryn [72]

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  Fig. 4.1  (continued) b Schematic and immunohistologic representations of the distribution of melanocyte subpopulations in different regions of the human anagen scalp hair follicle. Melanocytes in frozen scalp sections were detected using the antibody NKI/beteb to gp100. (B-AMc Bulbar amelanotic melanocyte, B-MMc bulbar melanogenic melanocyte, DP dermal papilla, Epi-Mc epidermal mela­ nocyte, HS hair shaft, IF infundibulum, ORS-AMc outer root sheath amelanogenic melanocyte, SG sebaceous gland.) Adapted from Tobin [69]

4

reotypic routes to enter the dermis of the skin. Melanogenesis occurs very early during human embryologic development and melanocytes can be detected in human skin as early as 7 weeks of gestation [24] with pigment synthesis some 5 months before birth. Indeed, some migrating melanoblasts/melanocytes are already melanogenically active in the murine dermis before arriving at the epidermis [48] and before hair follicle development commences [24]. Some melanoblasts proliferate and differentiate into melanocytes while residing in the epidermis, while others and their progeny, so-called transit-amplifying mela­ nocytes, leave the epidermis to distribute in the developing hair follicles as dopa-positive and dopa-negative cells in the hair follicle and its associated sebaceous gland. Melanogenic melanocytes and melanoblasts can be detected at all stages of hair morphogenesis, from the germ stage (Stage 2) onwards [48]. KIT-positive melanoblasts migrate into the hair follicle epithelium, which is a source of stem cell factor (SCF), and when differentiated target the hair bulb when it expresses SCF [48]. Once hair fiber formation commences, melanocytes concentrate at the basal lamina around the apex of the follicular dermal papilla, while KIT-negative amelanotic melanocytes/melanoblasts invade the outer root sheath and bulge region in the fully developed hair follicle [48]. Analysis of mutations that effect differentiation,

proliferation, and migration of melanocyte precursors in mice has helped to clarify the events involved in the development of melanocyte compartments within the skin and hair follicle. Of the more than 90 loci shown to affect hair color in the mouse [42], mutations in the receptor tyrosine kinase KIT and its cognate ligand SCF, and endothelin 3 and its receptor Ednrb have been most informative. Mutant homozygotes exhibit an almost complete lack of hair pigmentation. The importance of the KIT–SCF signaling pair is evident from the ability of a KIT-blocking antibody to induce apoptosis in murine follicular melanocytes [29].

4.3.2

Comparative Biology of Epidermal and Hair Follicle Melanocytes

The relative independence of the epidermal– and follicular–melanin units can be appreciated by the co-expression of white hair and black skin in aging Africans and conversely raven hair in white-skinned Europeans. This is further supported clinically, by the selective/preferential targeting of epidermal but not follicular melanocytes in most cases of vitiligo, while follicular melanocytes alone are damaged by immunemediated pathology in acute alopecia areata [70, 73]. In the fully developed anagen human scalp hair, follicle

Biology of Hair Follicle Pigmentation

melanocytes can be detected in distinct anatomic compartments with region-specific differentiation status (Figs. 4.1, 4.2). In the mature hair follicle, melanotic melanocytes positive for 3,4-dihydroxy phenylalanine (dopa) are readily detectable in the basal layer of the infundibulum and around the upper dermal papilla; moderately differentiated mela­nocytes may also be detected in the basal layer of the sebaceous gland. However, the hair bulb is the only site of pigment production for the hair shaft (Figs. 4.1, 4.2a,b), and contains both highly melanogenic melanocytes and a minor subpopulation of poorly differentiated melanocytes [69, 74]. Melanogenically active mela­nocytes are however restricted to the upper hair bulb matrix, just below the precortical keratinocytes, a location that facilitates the transfer of melanin to the hair shaft cortex, less so to the medulla, and very rarely the hair cuticle (Figs. 4.1, 4.2). The presence of immature melanocytes (melanoblasts) in fully developed adult anagen hair follicles has been confirmed in situ and in vitro [26, 69]. Dopa-negative amelanotic melanocytes appear in the mid-to-lower outer root sheath, but also in the periphery of the bulb and the most proximal matrix. All the dopa-positive cells, and also some dopa-negative melanocytes of the mid outer root sheath contain (pre)melanosomes (i.e., gp100-positive) [26]. Although amelanotic hair follicle melanocytes lack dopa-oxidase activity, low levels of the tyrosinase protein itself may be detected in some cells, as well as KIT and Bcl-2. These melanocytes do not express the melanogenic enzymes tyrosinase-related protein-1 (TRP1) and TRP2 (dopachrome tautomerase, DCT) [26]. The role of these amelanotic melanocytes in hair pigmentation is unclear, although it has been speculated that these cells represent a pool of “transient” melanocytes that migrate from precursor melanocyte stores in the upper outer root sheath [57, 79, 82]. This melanocyte pool may be targeted in an attempt to intervene biotechnologically in impaired hair pigmentation. This multi-functionality of follicular melanocyte subpopulations is further attested by their complex responses to chemotherapy [59, 79]. Recent immunologic data have shown that the “follicular–melanin unit” resides in the immune-privileged proximal anagen hair bulb (c.f. [65]). Melanocytes of the follicular–melanin unit are larger, more dendritic, have more extensive Golgi and rough endoplasmic reticulum (ER), and produce larger melanosomes compared to melanocytes in the epidermal–melanin unit (c.f. [72]). While melanin produced by the latter degrades almost completely in the differentiating layers of the epidermis, eumelanin granules transferred into hair cortical keratinocytes remain minimally digested; hence, the similarly pigmented proximal and distal ends of a typical hair shaft (c.f. [72]). By far the most striking difference between the epidermal– and follicular–melanin units, and

Chapter 4

one with significant implications for the regulation of hair pigmentation, is the observation that the activity of the hair bulb melanocyte is under tight cyclical control and that melanogenesis is coupled to the hair growth cycle (c.f. [56]). Epidermal melanogenesis, by contrast, appears to be continuous [44], though this constitutive activity can be stimulated further, e.g., after exposure to UV radiation.

4.3.3

The Fate of Hair Follicle Melanocytes During the Hair Growth Cycle

Active pigmentation occurs only during the hair growth phase (anagen) (Fig. 4.3a), which in human scalp hair can be very long (up to 8 years or more) [65]. This extended anagen of human scalp hair, together with its mosaic pattern of hair growth, hinders systematic analysis of melanocyte dynamics during the human hair cycle. However, the C57BL/6 mouse has proven to be a very useful model for human hair pigmentation, given their short anagen (15–17 days), synchronous hair growth pattern, restriction of melanogenically active truncal melanocytes to the hair follicles, exclusively eumelanin production, and the similar linkage of murine melanogenesis with anagen (Fig. 4.3b) [57]. The relatively quiescent telogen hair germ contains all cell precursors needed to reconstitute a fully developed anagen VI hair follicle. Tracking melanocyte subpopulations during the hair cycle has exploited the expression of melanogenesis-related proteins (or their mRNA) including tyrosinase, and related proteins TRP1 and DCT, in addition to KIT and the proliferation marker Ki67. In this way the extent of melanocyte differentiation can be followed both temporally during the hair cycle and physically throughout the different hair follicle anatomic compartments. During telogen C57BL/6 murine skin does not contain tyrosinase (mRNA or protein), TRP1 protein or melanin and has only very low levels of tyrosine hydroxylase activity [55]. Some melanocytes/melanoblasts from the telogen secondary germ are immunohistochemically positive for DCT, and, of these, a subpopulation also expresses KIT [9]. These melanocytes are mitotically quiescent, as assessed by Ki67 immunostaining. However, during the first 1 or 2 days of anagen induction some cells begin to express tyrosinase message and protein becomes barely detectable. During this time (i.e., anagen I) TRP1, and the tyrosine hydroxylase and dopa oxidase activities of tyrosinase remain undetectable enzymatically. However, some DCT-positive melanocytes begin to express TRP1 at this stage, especially melanocytes located close to the forming hair bulb, while melanocytes residing in the upper outer root sheath (site of the presumptive germ cell reservoir) remain TRP1 negative. A second subpopula-

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Biology of Hair Follicle Pigmentation

Chapter 4

9 Fig.  4.2a–e  Anatomy, histology and ultrastructure of the hair follicle pigmentary unit. a Intact pigmented anagen hair follicles isolated from normal human scalp tissue. Note the location of the intensely pigmented melanogenic zone (Mz) around the dermal papilla (DP). b Longitudinal section of human anagen scalp hair follicle. Note that melanocytes remain intensely pigmented and transfer melanin only to the precortical keratinocytes. (Co Cortex, CTS connective tissue sheath, DP dermal papilla, IRS inner root sheath, Mx matrix, ORS outer root sheath, dash line Auber’s Line.) c Transmission electron micrograph of a hair bulb melanocyte in a human scalp

anagen hair follicle. Note that cell contains large numbers of maturing and fully mature melanosomes and well-developed Golgi apparatus (arrow). d Transmission electron micrograph of part of a hair bulb melanocyte in a human scalp anagen hair follicle. Note the presence of early pre-melanosomes (I and II), maturing melanosomes (III) and fully mature ellipsoidal eumelanosomes (VI). e Transmission electron micrograph of a longitudinally sectioned hair shaft cortex revealing the distribution of melanin granules (Me) between cortical cells (Co) but not in the cuticle (Cu). Adapted from Tobin [70]

Fig. 4.3  a Schematic representation of the hair growth cycle. (APM Arrector pili muscle, BM basement membrane, DP dermal papilla, HM hair matrix, HS hair shaft, IRS inner root sheath, ORS outer root sheath, SG sebaceous gland.) Adapted

from Tobin & Paus [75]. b Depilated back of C57bl/6 mouse showing regions of the pelage in synchronous anagen (black), catagen (gray) and telogen (pale pink) stages of the hair growth cycle

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tion, which expresses TRP1 or DCT together with KIT, begins to show proliferative activity. The follicular papilla of early anagen hair follicles can pool high concentrations of l-phenylalanine, a potential requirement for the supply of l-tyrosine for melanogenesis [54]. Conditions that support the production of high amounts of l-tyrosine from l-phenylalanine include high levels of 6BH4, GTP-cyclohydrolase 1, and phenylalanine hydroxylase (PAH). All three are high from earliest anagen through to anagen III, after which the activities of all three drop significantly and remain low until the next telogen. Low 6BH4 levels may be necessary during pigment production to prevent its allosteric inhibition of tyrosinase. Just prior to this early anagen-associated drop (i.e., anagen II), tyrosinase message, protein, and activity all begin to increase rapidly to peak at early anagen VI (full anagen). Similarly, low thioredoxin reductase activities during anagen II and III promote more oxidizing conditions necessary for the initiation of melanogenesis. The gradual increase of thio­redoxin reductase during anagen V to catagen could neutralize reactive oxygen species (ROS) produced by melanogenesis (c.f. [54]). The anagen-associated stimulation of undifferentiated telogen melanocytes/melanoblasts predates the melanogenic stimulus delivered during anagen III, which in turn is followed by active melanogenesis and the subsequent transfer of mature melanosomes into keratinocytes of the precortical matrix. Melanocytes in the S-phase of the cell cycle have been reported as early as anagen II and significant proliferation is clearly apparent in anagen III [66]. Bulbar melanocytes during the transition from anagen III to anagen VI increase in number, in dendricity, develop more Golgi and rough endoplasmic reticulum, increase the size/number of their melanosomes, and begin to transfer mature melanosomes to precortical keratinocytes. By anagen IV, when the hair pigmentary unit becomes fully functional with respect to melanin synthesis, melanocytes are distributed into discrete locations throughout the hair follicle (Figs. 4.1, 4.2). Melanocytes localized to the murine HF bulge (site of presumptive reservoir) express only DCT, lacking TRP1, KIT, and Ki67 immunoreactivities. Melanocytes located in the elongating outer root sheath express DCT and KIT and in some cases are also positive for the proliferation marker Ki67, but express little TRP1 and no tyrosinase [9]. Only melanocytes distributing to the hair follicle melanogenic zone, i.e., the hair bulb matrix above the DP, express TRP1, DCT, tyrosinase, KIT, and also Ki67 in the majority of melanocytes. DCT protein is undetectable in melanogenic melanocytes of the human anagen hair bulb [12], highlighting an important speciesspecific difference with mice. Melanocyte proliferation ceases by anagen VI (full anagen). Both the activity and

 

concentration of tyrosinase remain constant during mid to late anagen VI, and decrease rapidly during the anagen VI to catagen transition phase, to become undetectable or very low in catagen [57]. The expression of other melanogenesis-related proteins follows a similar pattern. This physiologic decrease in follicular melanogenesis may reflect two possible mechanisms for termination of melanogenesis; namely, exhaustion of an active signaling system that stimulates melanogenesis, and/or the production of inhibitors of melanocyte activity [46, 61]. Even before catagen-associated structural changes are apparent in the hair bulb, the earliest signs of imminent hair follicle regression include the retraction of melanocyte dendrites and the attenuation of melanogenesis during late anagen VI [79]. Limited keratinocyte proliferation continues for a while, so the most proximal telogen hair shaft remains unpigmented – the functional relevance of which remains enigmatic. One can detect a dramatic and rapid drop in the levels of active tyrosinase beginning during late anagen VI itself, while DCT activity exhibits moderate reductions from mid to late anagen VI and is lowest during catagen. Pterin synthesis and PAH activities are low during catagen, while thio­redoxin reductase levels remain elevated to provide a reducing environment. This combination decreases l-tyrosine supply and so generates conditions unfavorable for active melanogenesis [54]. A long enduring enigma of both hair follicle and pigment biology concerns the fate of the hair bulb melanocytes when they become undetectable during catagen. Where do these melanocytes go during catagen and telogen? Where do they originate from when follicular melanogenesis is resumed during the next anagen phase? [79]. Until very recently, the dominant view was that the hair bulb melanocyte system is a self-perpetuating arrangement, whereby melanocytes involved in the pigmentation of one hair generation are also involved in the pigmentation of the next [66] via multiple cycles of de-differentiation followed by re-differentiation. While there is evidence of some plasticity in the hair follicle pigmentary unit, the level invoked by the self-perpetuating theory would imply a degree of plasticity not seen in most non-malignant cell systems. Moreover, fully differentiated bulbar melanocytes would also need to survive/avoid the extensive apoptosis-driven regression of the hair bulb [39] by actively suppressing apoptosis. Our current view suggests that many of the so-called re-differentiating melanocytes in early anagen correspond to newly recruited immature melanocytes derived from a melanocyte reservoir [43, 79] and are not reactivated from pre-existing hair bulb melanocytes that were melanogenically active during the previous anagen phase. This is supported by the observation of a population of immature DCT-positive melanocytes unaffected by blocking anti-KIT antibody in the murine bulge [9].

Biology of Hair Follicle Pigmentation

Chapter 4

These melanocyte “stem” cells are located at the base of the permanent part of the hair follicle and are immature, slow cycling, self-maintaining and are fully competent to regenerate progeny at early anagen [43]. Moreover, these hair follicle melanocyte stem cells appear to have the capacity to enter vacant niches, including (via migration to) the epidermis. It is possible, however, that some “new generation” melanogenically active melano-

cytes derive from a population of catagen-surviving melanocytes. Indeed, low numbers of apparently dendritic melanocytes can be detectable in the retreating epithelial strand of catagen hair follicles undergoing active resorption via apoptosis [11]. In any event at least a proportion of the highly melanotic (possibly terminally differentiated melanocytes) hair bulb melanocytes do not survive catagen [75]. Deletion of individual mela­

Fig.  4.4  a Schematic representation of an early catagen hair follicle. Note loss of some bulbar melanotic melanocytes via apoptosis. (Epi-Mc Epidermal melanocyte, IFN-Mc infundibular melanocyte, ORS Mc outer root sheath melanocyte.) b Transmission electron micrograph of section of an early catagen hair bulb showing apoptosis of two melanotic melanocytes (MCs). Inset: high-power view of premelanosomes. (DP Dermal papilla.) c Transmission electron micrograph of a section of an early catagen hair bulb showing a portion of a

Langerhans cell transporting melanin from the hair matrix to the follicular dermal papilla. Note rupture of the basal lamina (arrow). (Bl Basal lamina, DP follicular dermal papilla, Mx matrix.) d Uptake (phagocytosis/endocytosis) of melanin showing formation of a Langerhans granule at the plasma membrane. Adapted from [68, 72]. e Melanosomes within an endosome/ lysosome showing intimate relationship between Langerhans granule (arrow) and melanin granules

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notic melanocytes by apoptosis was confirmed using well-described ultrastructural features (Fig. 4.4a,b) and TUNEL/TRP-1 co-localization. Some pigment formed during late anagen fails to become incorporated into the hair shaft and instead is transported to the follicular papilla, epithelial strand or connective tissue sheath of catagen hair follicles. This redistribution of follicular pigment is likely to involve phagocytosis by macrophages, Langerhans cells, and follicular papilla fibroblasts, the first two of which increase in number during hair follicle regression (Fig. 4.4c–e).

4.3.4

Regulation of Pigmentation in the Hair Follicle

Pigmentation of hair fibers is affected by numerous intrinsic factors including: hair-cycle-dependent changes, body distribution, racial and gender differences, variable hormone responsiveness, genetic defects, and age-associated change. The multi-step nature of mela­ nosome biogenesis and melanogenesis involves several positive and negative regulators/factors including: growth factors, cytokines, hormones, neuropeptides and neurotransmitters, eicosanoids, cyclic nucleotides, nutrients, microelements, cations/anions, etc. [44]. These factors may act via autocrine, paracrine, and endocrine mechanisms, and while much of the available literature pertains to epidermal melanocytes (c.f. Slominski et al. [60]), similar regulators (except UVR) may also operate in follicular melanogenesis. Recent data, however, sug-

 

gest different roles for DCT and perhaps also TRP1 in human versus murine follicular melanocytes [7, 12]. The process of melanogenesis can be divided into: (1) melanosome biogenesis (Fig.  4.2c, d) and (2) the biochemical pathway that converts phenylalanine/ltyrosine into melanin (Fig. 4.5). Both processes are under complex genetic control, which encodes a range of enzymes, structural proteins, transcription factors, receptors, and growth factors. Melanosome structure correlates with the type of melanin produced. Melanocytes in black hair follicles contain the largest number of, and most electron-dense, melanosomes (eumelanosomes), each with a fibrillar matrix (c.f. [82]). Brown hair bulb melanocytes contain eumelanosomes that are somewhat smaller, but phenotypically similar to black hair melanosomes, while blonde hair bulbs produce weakly melanized melanosomes with often only the melanosomal matrix visible. Red hair pheomelanosomes, by contrast, contain a vesicular matrix with melanin deposited irregularly as blotches. Less is known about the events involved in the formation of the pheomelanosome that produces the red/yellow melanin, though tyrosinase activity may appear earlier in these melanosomes. Surprisingly, both eumelanogenic and pheomelanogenic melanosomes can co-exist in the same normal human melanocyte. The constitutive color of an individual’s hair is due to absolute tyrosinase activities, rather than levels of tyrosinase protein expression. Thus, tyrosinase regulation is critical, being controlled not only by the supply of l-tyrosine but also by the stability/activity of tyrosinase and

Fig. 4.5  Biosynthesis of melanins. There is some debate about some of the finer details of this pathway, especially whether the enzyme tyrosine hydroxylase (in addition to tyrosinase) can convert ltyrosine to l-dopa in the melanocyte and whether PKC-beta can be described as a rate-limiting enzyme for melanogenesis via its ability to activate tyrosinase. [ASP Agouti signaling protein, 6BH4 (6R)l–erythro-5,6,7,8-tetrahydrobiopterin, DCT dopachrome tautomerase, DHICA 5,6-dihydroxyindole-2-carboxylic acid, l-dopa l-3,4-Dihydroxyphenylalanine, MC1R melanocortin 1 receptor, MSH melanocyte stimulating hormone, TRP tyrosinase-related protein. Adapted from Tobin [71].

Biology of Hair Follicle Pigmentation

tyrosinase-related proteins. Both l-phenylalanine and l-tyrosine can access the melanocyte, the former via the neutral amino acid Na+/Ca2+ ATPase anti-porter system and the latter by facilitated diffusion. l-Phenylalanine is converted to l-tyrosine via phenylalanine dehydroxylase (PAH) activity, and PAH activities have been found to correlate positively with skin phototypes. Melanogenesis regulation also involves hormones, neurotransmitters, cytokines, growth factors, eicosanoids, cyclic nucleo­ tides, nutrients, and the physicochemical milieu [60]. These act sequentially or in parallel, through pathways involving activation of G-protein receptors, receptors coupled to kinase activities or nuclear receptors. The predominant modifier and inhibitor of melanin synthesis in animal (though not in human) hair follicles is agouti protein (ASP) [5]. In mouse the transient synthesis of ASP switches eumelanogenesis to pheomelanogenesis, a change that can be associated with decreased tyrosinase activity [5]. The agouti protein ASP also acts as a direct antagonist to melanocortins and as an inverse agonist at the MC1R [5], being both a qualitative modulator and an inhibitor of melanogenesis. Among the factors modifying ASP action are mahogany (mg) or Attractin (Atrn) (required for ASP action) and mahoganoid (md), also known as Mahogunin (Mgrn1), which prevents hair follicle melanocytes from responding to ASP [21]. Studies have documented that signal transduction pathways involving peptides derived from pro-opiomelanocortin (POMC), SCF/KIT and ET1, ET3/ETA, and ETB play a crucial role in normal follicular melanogenesis [29, 60, 71]. Their pro-pigmentary activity is initiated by the binding of locally produced POMCderived ACTH, α-MSH, and β-MSH peptides. For example, α-MSH increases the proportion of black to gray hairs when administered intramuscularly in the guinea pig [62]. The cognate receptor of α-MSH is MC1R, an important positive regulator of hair pigmentation [50]. This G-protein-coupled membrane receptor is activated upon binding of POMC-derived ACTH, α-MSH, and β-MSH peptides. The resultant signal transduction cascade activates adenylate cyclase, leading to subsequent cAMP production, which results in increased melanocyte proliferation, melanogenesis, and dendrite formation. However, while injection of α-MSH into human skin increased epidermal melanogenesis, particularly of sun-exposed skin, no effect was seen in hair follicles [38]. This is supported by the failure to detect significant expression of free α-MSH peptide in pigmented human hair bulb melanocytes, in contrast to their epidermal counterparts [33]. Humans with POMC gene mutations may have red-hair phenotype [51]. A POMC/MC1R complementary system, the β-endorphin/µ-opiate receptor system, also participates in the regulation of both human epidermal and follicular melanocyte biology, by inducing changes in dendric-

Chapter 4

ity, proliferation, and melanogenesis [32]. The underlying mechanism involved here remains unclear, given that signaling through the µ-opiate receptor results in a downregulation of cAMP [71]. Recently we have also examined the most proximal element of the hypothalamus–pituitary–adrenal axis, i.e., corticotropin-releasing hormone (CRH), in the regulation of melanogenesis. Like POMC, CRH is also produced locally in the human skin [58], and can modify the phenotype of human hair follicle melanocytes in vitro by upregulating cell dendricity and pigmentation levels [34]. The basis for this activity remains to be established, and it could reflect direct (i.e., via CRH receptors) or indirect (i.e., via CRH induction of POMC peptides, e.g., ACTH) effects. Given the similar biogenic derivation of melanosomes and lysosomes, it is notable that the lack of some lysosomal enzymes can affect the hair follicle pigmentary unit. For example, in the absence of the papain-like lysosomal cysteine protease cathepsin L (CTSL), hair bulb melanocytes can exhibit marked vacuolation during melanosome organellogenesis, suggesting that these organelles may become unstable in the absence of this lysosomal enzyme [82].

4.3.5

Aging of the Follicle Melanocytes and Hair Graying (Canities)

For every decade after 30 years of age the number of pigment-producing melanocytes in exposed/unexposed epidermis decreases by 10%–20% [85], accounting for much of the loss of skin tone with age. Nevertheless, epidermal melanocytes are relatively long-living cells, protected in part from reactive oxygen species (including those generated during melanogenesis) by their high expression of anti-apoptotic cell survival factors, e.g., bcl-2. Hair color shows striking age-related changes, particularly in those of Eurasian origin. During puberty there is often a switch from fair “intermediate” hair to more deeply pigmented, coarser “terminal” hair. Furthermore, hair fiber heterochromia may become more apparent with age, most strikingly for scalp and beard [36]. However, the most dramatic age-related change in hair pigment is the onset of hair graying or canities, which is the gradual age-dependent dilution of hair color to gray or white, also known as senile canities. The increasing longevity of human life inevitably means we will spend an increasing proportion of our lives sporting this sign of lost youth. Canities/graying first appears in our 30s, and so is unlikely to have exerted significant evolutionary selective pressure, occurring as it does after reproductive peak age. The examination of melanocyte aging has only recently been pursued with any particular vigor. Clinical observation suggests that the follicular- and epidermal-

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melanin units have a different “melanogenetic clock.” It has been observed that loss of melanocyte replicative potential in vitro is associated not only with increasing age of the donor but also with the melanin content of the cell. This becomes very apparent after long-term continuous exposure to cAMP inducers (e.g., cholera toxin), which induce pigment without directly engaging the MC1R [6]. Similarly, millimolar l-tyrosine (a melanin precursor) abrogates proliferation in cultured “presenescent” pigmented melanocytes, with proliferation continuing only in resistant amelanotic cells [6]. On reaching senescence, melanocytes express increased levels of cyclin-dependent kinase (CDK) inhibitors, e.g., p21 and p16, which inhibit cell cycling. Accumulation of oxidative damage is an important determinant of the rate of cell aging, although it is unclear whether it is the primary cause of aging. It is likely that the antioxidant systems within the hair follicle melanocyte become impaired with age, leading to uncontrolled damage to the melanocyte itself from its own melanogenesis-related oxidative stress. In addition, melanin synthesis, by its very nature, produces mutagenic intermediates. Reactive oxygen species (ROS) can damage DNA (both nuclear and mitochondrial), result in the accumulation of mutations, and can induce both oxidative stress and antioxidant mechanisms. Thus, the induction of replicative senescence in melanogenic hair bulb melanocytes may be an important protective mechanism against cell transformation. The extraordinary melanogenic activity of pigmented bulbar melanocytes (up to 10 years in some scalp hair follicles) is likely to generate large amounts of ROS via the oxidation of tyrosine and dopa to melanin [22]. If not adequately removed, an accumulation of these ROS may generate significant oxidative stress in both the melanocyte itself and in the highly proliferative anagen hair bulb epithelium. Thus, in these circumstances, melanogenic bulbar melanocytes are perhaps best suited to assume a postmitotic, terminally differentiated “(pre)senescence” status to prevent cell transformation. Recent work suggests that the follicular–melanin unit of graying hair is associated with increased melanocyte apoptosis and oxidative stress [4]. Moreover, this study also reported that the “common” deletion in mitochondrial DNA (associated with oxidative stress) occurred more prominently in graying compared to normally pigmented hair follicles. Graying hair follicles were also less well equipped to handle an exogenous oxidative stress, which is likely to be the result of impaired antioxidant mechanisms. A characteristic feature of bulbar melanocytes is their extremely high melanin load and phenomenal synthetic capacity for melanin production (Fig. 4.2). A relatively small number of melanocytes (0.5 cm: quality (Q; scored 1–3), density (D; 0–3), proportion of zone covered with hair (P; 0–1), giving a total score (Q×D×P)

Ferriman and Gallwey (1961) [26]

11

Quantitative score based upon distribution of hair on each site (see Fig. 8.2)

Lorenzo (1970) [50]

7

Quantitative score based upon density and extent of involvement

Hatch et al. (1981) [38]

9

Quantitative score based on distribution of hair on each site

Lunde (1984) [52]

18

Quantitative assessment of length and density of terminal hairs >0.5 cm

8.3.2.1 Ferriman and Gallwey Score 8.3.2.1.1 Introduction The Ferriman–Gallwey scoring system is an easily and the most widely used tool for the evaluation and quantification of hirsutism in women. It was developed by Ferriman and Gallwey in 1961 for anthropological research [26]. Today the modified Ferriman–Gallwey score (mFG) evaluates nine regions for their degree and nature of body hair growth from 0 to 4. On the basis of a draft scale the body regions are compared and a score above 8 is a strong sign for hirsutism. It is not applicable in Asia due to ethnical variation in hair growth.

8.3.2.1.2 Technology 8.3.2.1.2.1 Indication Excessive facial and body hair growth with male pattern distribution in women is indicative of hirsutism, who require a semi-quantitative method to estimate their hair growth intensity and for follow-up under therapy.

8.3.2.1.2.2 Technical Procedure For the original Ferriman-Gallwey score 11 body regions are rated from 0 (absence of terminal hair) to 4

(very distinctive terminal hair growth). The sites are: upper lip, chin, chest, upper back, lower back, upper abdomen, lower abdomen, arm, forearm, thigh, and leg (Fig. 8.2). Today, a mFG score rating only nine regions, leaving leg and forearm unconsidered, is the most frequently used evaluation method. This score evaluates excessive hair growth with a male pattern. All nine face and body regions are judged with a score of 0–4 and all points are summed; today in daily practice a score >6, in certain countries >8, is considered as hirsutism. However, there is no standard value that defines a threshold for hir­ sutism. Ferriman and Gallwey took a sum of above 5 as representative for abnormal hair growth and a valuable indicator of hirsutism [20]. Other studies took scores of between 6 [77] and 10. The Abraham’s classification stages a patient’s degree of hirsutism (see Chap 17, Table 17.1).

8.3.2.1.2.3 Complications To confidently establish observer conformity is difficult, due both to the lack of method standardization [2] and the fact that most patients have epilated, waxed, shaved or used other techniques to remove their hair before their consultation, meaning that the clinician cannot rate them correctly by face and body examination. However, Hahn et al. [36] report rather good reproducibility and reliability when patients self-evaluate.

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8

Fig. 8.2  Modified Ferriman-Gallwey score (mF6) [67]: Nine body regions are evaluated for their degree of hair growth from 0–4. A total score >8 is a sign for hirsutism

8.3.2.1.2.4 Combination Possibilities and Practical Advice The mFG can be combined with photographic documentation and a phototrichogram or TrichoScan in clinical studies. The mFG score can be used to evaluate the severity of hirsutism and to follow-up the hair growth activity under different therapeutic regimens.

8.4

Hair Growth

8.4.1

Hair Pull Test

8.4.1.1 Introduction The hair pull test is a simple test for the clinician to determine the ongoing activity and severity of any kind of hair loss. The pull test technique shows rather high interexaminer variability; however, each examiner stand­ ardizes his or her own procedure and has benchmarks for assessing patients.

8.4.1.2 Technology 8.4.1.2.1 Indication The pull test helps to roughly estimate the severity of hair loss in daily practice with a high interobserver variability. Its range of application in the diagnostic process reaches from androgenetic alopecia and alopecia areata, to diffuse effluvium, to scarring alopecia.

8.4.1.2.2 Technical Procedure A bundle of about 50–60 hairs is grasped between the thumb, index finger, and middle finger from the base near the scalp. The hair is firmly, but not forcibly, tugged away from the scalp as fingers slide along the hair shaft [76]. Another procedure is to use both hands, and grasp a tuft of hair between two fingers of one hand and pull at it with the other [33]. Afterwards the number of extracted hairs is counted and, depending on the diagnosis, sometimes examined under the microscope, e.g., in loose anagen hair. If more than 10% of grasped hairs, or six hairs, are pulled away from the scalp, this constitutes a positive

Hair Growth Assessment Techniques

pull test and implies active hair shedding. If fewer than six hairs can be easily pulled out, this is considered normal physiologic shedding [76]. The same procedure is repeated in four scalp areas (right + left parietal and frontal + occipital areas). To standardize the test and to obtain comparable results, patients are asked to refrain from washing their hair in the 5 days before the examination; however, some clinicians have a standard 2-day period between shampooing and the pull test, although it is important that they make this clear when reporting the results. The pull test is normally negative on the day of shampooing as all telogen hairs have been rinsed away. Despite these requests, most patients come to the office having just shampooed their hair, or they do not ad-

Chapter 8

here to the guidance on the interval from the last shampooing required (Fig. 8.3a,b) (Table 8.3).

8.4.1.2.3 Complications Discrepancies may arise because of differences in pulling strength, and in the density or thickness of hair shafts. The pull test is a very rough method and difficult to stand­ardize, as it is subject to high interindividual variation among investigators. The pulling force is not distributed uniformly all over the whole hair bundle, which creates variation from one hair to another. It seems to be useful only in acute phases of hair loss in the more severe conditions [83].

Table 8.3  Pull test (PT) results and the corresponding hair disease [76, 78, 90] Disease

Hair pull test

Normal

0–5 hairs can be pulled; a test with ≥6 hairs is positive

Alopecia areata

Positive, ≥6 hairs on light microscopy show dystrophic anagen and telogen stage

Androgenetic alopecia

Mostly normal. In active AGA, positive on the top of the scalp; negative in occipital area

Acute anagen or telogen effluvium

Positive in active phases with increased numbers of anagen or anagen dysplastic hairs or normal telogen hairs

Chronic telogen effluvium (CTE)

Positive only in active phase of CTE always with 6–8 telogen roots when examined with light microscopy

Trichotillomania

Negative with no pluckable hairs

Loose anagen syndrome

Highly positive; up to 100% when hairs are examined under the microscope; anagen hair root mostly lacking the hair sheath (anagen dysplastic)

Fig. 8.3a,b  A bundle of hairs is grasped between two fingers. A constant traction force in the direction of hair growth is used to pull out slightly adhered hairs from the hair follicles

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8.4.1.2.4 Combination Possibilities and Practical Advice

8

The hairs that are pulled out can be analyzed by light microscopy to narrow the differential diagnosis. The pull test is only a rough approach to diagnosis and can be used during the trichological examination. However, more reliable tests and objective measurements should be added where necessary. The hair pull test seems to be useful for the practitioner for diagnosis and therapeutic follow-up; however, it is not suitable for use in clinical studies. If the same investigator always uses the pull test in the same way, it is useful for him or her when routinely used in patient follow-up.

8.4.2

Wash Test (Modified)

8.4.2.1 Introduction The wash test was first introduced to quantify the amount of hair lost under standardized washing conditions. It is a non-invasive method to measure hair loss by counting and identifying rinsed out hairs. The wash test was modified by Rebora et al. [65] as the so-called AGA/TE wash test in order to distinguish between AGA and telogen effluvium (TE), by counting the number of vellus and terminal telogen hairs rinsed out on washing.

8.4.2.2 Technology 8.4.2.2.1 Indication The modified AGA/TE wash test is used to measure the severity of hair loss in TE or AGA.

8.4.2.2.2 Technical Procedure After a 5-day abstention from shampooing, the patients wash and rinse their hair in a basin whose hole is covered by gauze to entrap the lost hairs. Hairs are then collected in a paper envelope and brought to the examiner for hair count and further analyses. For the AGA/TE modified wash test, the hairs are counted and divided into three classes of hair length: (1) long hair >5 cm, (2) intermediate hair (>3 to A androgen receptor polymorphism [23].

9.8

9

Management

Male balding is a biologically normal process. Under normal circumstances it has no adverse effect on physical wellbeing apart from increasing the risk of chronic photodamage to unprotected scalp skin. Under exceptional conditions a full head of hair may also contribute to thermoregulation: the French military surgeon Dominique-Jean Larrey observed that the bald men (and men without hats) were the first to die during the Russian campaign in the winter of 1812. Yet balding still has a powerful effect on the human psyche, to the extent that few men would choose to go bald were the choice available. Many men accept loss of their hair and prefer to let nature take its course. However, for some men balding is important enough for them to seek treatment and for a few concern about hair loss reaches the level of a body dysmorphic disorder. It is important to recognize men in the latter group, as treatment aimed at addressing the perceived hair problem is unlikely to be successful. A number of studies have shown that male balding has an adverse effect on quality of life (though this is almost inevitable in those seeking professional advice). Nevertheless, balding is often seen as a trivial issue (mainly by non-sufferers) which may make men reluctant to approach their physician as they perceive, rightly or wrongly, that they will not receive a sympathetic response.

9.8.1

Counselling

Men seeking medical advice for male balding fall roughly into three groups (which may overlap): those who wish to ensure their hair loss is not a manifestation of an underlying serious disease, those who wish to be treated and those with a body image problem. For all groups counselling should include an explanation of the nature of male balding and its natural history. For those interested in preventing further progression or improving their hair status the treatment options will also need to be discussed. For those with a body dysmorphic disorder involvement of a clinical psychologist or psychia-

 

trist should be explored. Hair loss is an emotive issue and sufferers are vulnerable to exploitation by the unscrupulous. Patients should be advised against parting with large sums of money on unproven and valueless remedies.

9.8.2

Medical Treatments

At present only two medical treatments, minoxidil and finasteride, are of proven benefit in male balding. Both drugs will stimulate some regrowth of hair in some men but are perhaps better regarded as preventative treatments. Neither will regrow hair on completely bald scalp and continued treatment is necessary to maintain the response. Both drugs have a good safety record, a consideration of paramount importance when treating hair growth disorders.

9.8.2.1 Minoxidil Minoxidil was licensed as an oral drug to treat hypertension in the early 1970s. It soon became apparent that a high proportion of those taking minoxidil tablets developed significant hypertrichosis, a side-effect that has almost eliminated its use as an anti-hypertensive agent. Following a report of increased hair growth on the scalp of a balding man taking minoxidil tablets [69], extemporaneous formulations of minoxidil lotion were developed for topical application in the treatment of hair loss (initial reports concentrated mainly on alopecia areata). A 2% formulation of minoxidil lotion was subsequently licensed by the American Food and Drug Administration for the treatment of male balding and marketed by the Upjohn Company in 1986. A 5% formulation was marketed in 1993. The recommended dose is 1 ml twice daily (for both 2% and 5% formulations). The mechanism of action of minoxidil on hair growth is uncertain [42]. There is convincing evidence that its vasorelaxant activity is due to opening of ATP-sensitive potassium channels (KATP channels) in the sarcolemma of vascular smooth muscle cells. There is circumstantial evidence that its effect on hair growth is also due to opening of KATP channels but direct proof is lacking and it is unclear how this action modulates hair growth. The rapid response of hair growth to minoxidil suggests that the drug acts mainly to promote entry into anagen of follicles in a latent stage of the hair cycle. There is no convincing evidence that minoxidil reverses follicular miniaturization although it may prevent or delay it. Clinical trials using various endpoints, including hair counts, hair weight and global photography, have confirmed improvement in male balding with the use of minoxidil lotion [48, 54]. The mean increase in target area

Male Androgenetic Alopecia

hair counts is about 8% with 2% minoxidil lotion and 10%–12% with the 5% formulation. When assessed by global photography nearly 60% of men show improvement with 5% minoxidil lotion and 40% with 2%, compared to 23% with placebo. The response to minoxidil in terms of increased hair counts and hair weight is rapid and peaks by 16 weeks although the cosmetic response may take longer to become apparent. Trials continued for up to 2 years suggest the improvement is sustained providing treatment is maintained. Any positive effect on hair growth is lost within 4–6 months of stopping treatment [47, 54]. Adverse effects of minoxidil are mainly dermatological. Constituents of the vehicle occasionally cause scalp irritation, more commonly with the 5% formulation. Allergic reactions to minoxidil or propylene glycol (a component of the vehicle) are rare but necessitate stopping treatment. Some patients notice an increase in hair shedding 2–8 weeks after starting treatment. This is selflimiting but patients should be forewarned not to stop treatment if this happens. A new topical foam preparation containing 5% minoxidil has recently been approved for use in men by the USA Food and Drug Administration. It is less messy than the current lotion formulation and is potentially less irritant as it does not contain propylene glycol. The results of clinical trials are awaited.

9.8.2.2 Finasteride Finasteride is a competitive inhibitor of type 2 5α-reductase. Taken orally it reduces DHT levels in serum and in scalp by up to 70% [12]. Large-scale and long-term placebo-controlled studies using hair count and global photographic technology show that finasteride (1 mg daily) prevents or slows the progression of male balding in most men and about two-thirds experience some improvement [34]. The improvement peaks at around 12 months and, on average, there is some decline after 2 years. However, after 5  years those on placebo continued to lose hair more rapidly than those on finasteride [59]. Clinical trials have shown a small increase in sexual dysfunction (e.g. impotence) in men taking finasteride for male balding (4.2% versus 2.2% for placebo in young men [34], 8.7% versus 5.1% in older men [12]). These side-effects resolve on discontinuation of the drug. The level of finasteride in semen is very low and poses no risk to a male fetus in a pregnant sexual partner. Data from a long-term trial in 18,882 men aged over 54 taking 5 mg finasteride daily or placebo showed a 25% overall reduction in the incidence of prostatic cancer in those taking finasteride but a small increase in the frequency of highgrade prostatic cancer [65]. The relevance of this finding

Chapter 9

to men taking 1 mg daily for male balding is unknown but it is advisable to warn patients of this uncertainty.

9.8.2.3 Minoxidil versus Finasteride There are no blinded controlled trials comparing the response of male balding to minoxidil lotion and oral finasteride although one open study reported a greater degree of improvement in men taking finasteride compared to those using 5% minoxidil lotion [2]. In practice the decision comes down to patient preference. On the one hand, minoxidil is a little cheaper and it has been in use for longer so more is known about long-term safety. On the other hand, it is more convenient to take a single tablet of finasteride daily than apply a lotion twice daily to the scalp. We do not know whether the combination of minoxidil and finasteride confers any advantage over either drug used singly. The mechanisms of action are different so, on a superficial level, one might expect at least a partially additive effect. However, their outcomes in terms of their effects on the dynamics of hair growth are probably the same.

9.8.3

Surgery

Surgical treatment of male balding involves the redistribution of terminal hair to cover balding scalp – the number of terminal hair follicles on the scalp remains the same. In most cases this means transplanting hair follicles from the occipital scalp to the balding areas. Other techniques, such as excising the balding skin (scalp reduction) and rotational flaps are now less widely used. Surgical treatment can achieve very satisfactory results but careful patient selection and surgical skill allied to the aesthetics of scalp hair growth are essential. A detailed review of the indications and techniques of hair surgery is beyond the scope of this article (see Chap. 22). However, key considerations include the following [49]: „„ There should be an adequate donor area, i.e. good

hair density in the occipital scalp

„„ Age: the predictive value for men aged A androgen receptor polymorphism is associated with a decreased risk of metastatic prostate cancer and androgenetic alopecia. Cancer Epidemiol Biomarkers Prev; 14: 993-6 Herrera CR, D’Agostino RB, Gerstman BB et al (1995) Baldness and coronary heart disease rates in men from the Framingham Study. Am J Epidemiol; 142: 828-33 Hillmer AM, Hanneken S, Ritzmann S et al (2005) Genetic variation in the human androgen receptor gene is the major determinant of common early-onset androgenetic alopecia. Am J Hum Genet; 77: 140-8 Hsieh CC, Thanos A, Mitropoulos D et al (1999) Risk factors for prostate cancer: a case-control study in Greece. Int J Cancer; 80: 699-703 Imperato-McGinley J (2002) 5alpha-reductase-2 deficiency and complete androgen insensitivity: lessons from nature. Adv Exp Med Biol; 511: 121-31; discussion 31-4 Imperato-McGinley J, Miller M, Wilson JD et al (1991) A cluster of male pseudohermaphrodites with 5 alphareductase deficiency in Papua New Guinea. Clin Endocrinol (Oxf); 34: 293-8 Inui S, Fukuzato Y, Nakajima T et al (2002) Androgeninducible TGF-beta1 from balding dermal papilla cells inhibits epithelial cell growth: a clue to understand paradoxical effects of androgen on human hair growth. FASEB J; 16: 1967-9 Itami S, Kurata S, Sonoda T et al (1991) Characterization of 5 alpha-reductase in cultured human dermal papilla cells from beard and occipital scalp hair. J Invest Dermatol; 96: 57-60

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67. 68.

69.

Setty LR (1970) Hair patterns of scalp of white and Negro males. Am J Phys Anthropol; 33: 49-55 Shapiro J, Kaufman KD (2003) Use of finasteride in the treatment of men with androgenetic alopecia (male pattern hair loss). J Investigat Dermatol Symp Proc 8: 20-3 Sigelman L, Dawson A, Nitz M et al (1990) Hair loss and electability: the bald truth. J Nonverbal Behav; 14: 269-83 Smith MA, Wells RS (1964) Male-type alopecia, alopecia areata, and normal hair in women. Arch Dermatol; 89: 155-8 Sreekumar GP, Pardinas J, Wong CQ et al (1999) Serum androgens and genetic linkage analysis in early onset androgenetic alopecia. J Invest Dermatol; 113: 277-9 Thigpen AE, Davis DL, Milatovich A et al (1992) Molecu­lar genetics of steroid 5 alpha-reductase 2 deficiency. J Clin Invest; 90: 799-809 Thigpen AE, Silver RI, Guileyardo JM et al (1993) Tissue distribution and ontogeny of steroid 5 alpha-reductase isozyme expression. J Clin Invest; 92: 903-10 Thompson IM, Goodman PJ, Tangen CM et al (2003) The influence of finasteride on the development of prostate cancer. N Engl J Med; 349: 215-24 Van Scott EJ, Ekel TM (1958) Geometric relationships between the matrix of the hair bulb and its dermal papilla in normal and alopecic scalp. J Invest Dermatol; 31: 281-7 West PM, Packer C (2002) Sexual selection, temperature, and the lion’s mane. Science; 297: 1339-43 Whiting DA (1993) Diagnostic and predictive value of horizontal sections of scalp biopsy specimens in male pattern androgenetic alopecia. J Am Acad Dermatol; 28: 755-63 Zappacosta AR (1980) Reversal of baldness in patient receiving minoxidil for hypertension. N Engl J Med; 303: 1480-1

Chapter 10

10

Female Pattern Hair Loss Elise A. Olsen

 

 

6

Synonyms female pattern hair loss, androgenetic alopecia, an­ drogenic alopecia, common baldness in women, diffuse alopecia in women, female pattern baldness, diffuse hormonal alopecia



Key Features

• Decrease in hair density in the central (vertex, mid

and frontal) scalp, bitemporal and parietal regions in women. Miniaturization of affected hairs. Two ages of onset: early (post-puberty to third decade) and late (age 40+ years). Signs of hyperandrogenism (hirsutism, irregular periods) or hyperandrogenemia occur in a subset of women with female pattern hair loss (FPHL) but most women with FPHL have neither.

• • •

• Many, but not all, affected women respond to antiandrogens or 5α-reductase inhibitors with increased hair growth indicating an androgen etiology in at least some cases of FPHL.

 

Contents 10.1 10.2 10.3 10.4 10.4.1 10.4.2 10.4.3 10.5 10.6 10.7 10.8 10.9 10.9.1

Introduction   . . . . . . . . . . . . . . . . . . . . . . . . History  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology   . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology   . . . . . . . . . . . . . . . . . . . . . Androgens   . . . . . . . . . . . . . . . . . . . . . . . . . . Estrogens   . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetics  . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features   . . . . . . . . . . . . . . . . . . . . . Histopathology  . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis   . . . . . . . . . . . . . . . . Evaluation   . . . . . . . . . . . . . . . . . . . . . . . . . . Medical Treatment   . . . . . . . . . . . . . . . . . . . Topical Minoxidil   . . . . . . . . . . . . . . . . . . . .

  172   172   173   173   173   175   176   176   177   177   178   179   179

10.9.2 10.9.3 10.9.4 10.9.5 10.9.6 10.9.7 10.9.8 10.9.9 10.9.10 10.10

Antiandrogens   . . . . . . . . . . . . . . . . . . . . . . Spironolactone   . . . . . . . . . . . . . . . . . . . . . . Flutamide   . . . . . . . . . . . . . . . . . . . . . . . . . . Cyproterone Acetate   . . . . . . . . . . . . . . . . . Other Antiandrogens   . . . . . . . . . . . . . . . . . 5α-Reductase Inhibitors   . . . . . . . . . . . . . . Estrogens   . . . . . . . . . . . . . . . . . . . . . . . . . . . Estrogen Receptor Antagonist   . . . . . . . . . Melatonin  . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgical Treatment  . . . . . . . . . . . . . . . . . . . Summary for the Clinician  . . . . . . . . . . . . .

  180   180   181   181   182   182   182   182   182   183   183

References   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   183

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10.1

10

Introduction

Female pattern hair loss (FPHL) is a broad term for the decrease in central scalp hair density that occurs in many females post puberty [62]. Many other terms have been used for this particular type of alopecia including androgenetic alopecia (AGA) and androgenic alopecia, both terms which imply a specific androgen-related and genetic etiology. While certainly a proportion of women with this hair phenotype have the female counterpart of male AGA, i.e., they clearly respond with hair growth to antiandrogens or 5α-reductase inhibitors, it has not been proven that all women with this pattern of hair loss clearly have an androgen-related process [62]. Therefore, the term FPHL, while inclusive of AGA in women, allows for further thought and research on this hair loss condition without implying causality. FPHL affects >50% of women over the age of 50 years and while the hair loss may seem trivial to the observer, it is often emotionally devastating for the affected women. FPHL may occur alone or may be part of a constellation of androgen-related conditions. The diagnosis of FPHL is not clear-cut as it is in men with male pattern hair loss (MPHL) but requires a history, physical exam, laboratory work, and often a scalp biopsy to differentiate it from other causes of hair loss. Current treatments for FPHL are limited in number and degree of efficacy.

10.2

 

casian women, Hamilton noted that this hair loss in women never progressed further than a pattern IV (see Chap. 9) and that in most cases only to a pattern II limited to bitemporal recession [39]. Although he showed that MPHL was androgen related [38] he questioned whether androgens were clearly causal in FPHL [39]. Maguire and Kligman in a seminal article on common baldness in 1963 [52] and Ludwig in 1964 [50] claimed that male and female pattern hair loss had the same etiology (genetic predisposition and androgen stimulation) but that women did not usually have frontotemporal recession as seen commonly with men. Ludwig in 1977 described the progressive centrifugal hair loss with preservation of the frontal hair line to which he assigned three pictorial gradations of severity [51] (Fig. 10.1). Olsen commented on the frequent Christmas tree pattern of FPHL with frontal accentuation [59, 61, 69] (Fig. 10.2). Ludwig suggested the term “female type of androgenetic alopecia” to include causality, but more recently a consensus meeting of specialists in hair and reproductive endocrinology proposed the term FPHL to describe the hair phenotype in women with or without an obvious androgen relatedness [62].

History

Beek in 1950 noted that baldness and calvities frontalis in women increased dramatically from the fourth to the sixth decades [6]. In his 1951 review of 214 Cau-

Fig. 10.1  Ludwig patterns of hair loss (reprinted with permission from Olsen [62])

Fig. 10.2  Woman with frontal accentuation of hair loss

Female Pattern Hair Loss

10.3

Epidemiology

The comparative prevalence of the three clinical patterns of FPHL (Fig. 10.3) is unknown. However, Hamilton [39] noted a male pattern of deep frontotemporal recession usually with some loss of the midfrontal border of the scalp in 19% of women with no increase in those over the age of 50. Olsen [61] noted a frontal accentuation pattern but usually with preservation of the frontal hair line in 48% of women age 15–70 presenting to clinic with FPHL (Fig. 10.4). The Ludwig pattern of FPHL has more commonly been used to examine the prevalence of FPHL but the information on prevalence using this has varied widely. Venning and Dawber found that 87% of 254 premenopausal women and 63% of 310 postmenopausal women without specific complaints of hair loss had Ludwig I-III hair loss [104]. These percentages seem unusually high for young women and Birch et al. in evaluating 377 women presenting to a dermatology clinic with complaints unrelated to hair loss reported a 6% incidence of the Ludwig pattern in women under the age of 50 years and 38% in women ≥70 years [8]. Norwood confirmed the increasing incidence of FPHL with age although no description of the criteria for the diagnosis was given: 14% of 568 women under 50 years old compared to 26% of 438 women over 50 years old [57]. Gan and Sinclair (Fig. 10.5) used a photographic scale to pictorially grade FPHL hair loss and determined that 53 of 267 (20%) of women under 50 had FPHL (defined as >Stage II) compared to 90/450 (42%) of women over 50 [32]. Clearly, there are racial differences with less FPHL reported in women of oriental compared to European descent [75]. The incidence of FPHL in women of African descent is difficult to determine, at least in the United States, secondary to the frequent overlap of central centrifugal cicatricial alopecia [65].

Chapter 10

10.4

173

Pathophysiology

10.4.1 Androgens Circulating androgens in women come from three potential sources: adrenal, ovary, and peripheral conversion. Availability in the hair follicle of testosterone (T) and dihydrotestosterone (DHT), the primary androgens causing cellular androgen-related effects, depends on an intact central (gonadal or adrenal) steroid biosynthetic pathway that will take synthesis to at least dehydroepiandrosterone sulfate (DHEA-S) (Fig. 10.6) [41] as well as the presence of the terminal conversion enzymes of steroid sulfatase, 17β-hydoxysteroid dehydrogenase, 5α-reductase, and 3β-hydroxysteroid dehydrogenase. All these enzymes are potentially available in the follicle itself [16]. Androgens circulate in the blood either free or preferentially bound to sex-hormone-binding globulin (SHBG) (78%), albumin (20%) or cortisol-binding globulin or acid α-2 glycoprotein (30 years old was 54% and in female relatives over 30 years old was 21% [91]. The androgen receptor is on the X chromosome, which could explain the mosaic effect on the hair follicles in the involved scalp in women with FPHL versus an effect on all follicles in the involved scalp in men with MPHL. However, men with MPHL have a strong paternal history of MPHL which does not support an X chromosome inheritance for both male and female pattern hair loss. It is likely that early and late FPHL are distinct genetically and that the cause of FPHL is polygenic and multifactorial.

10.5

Clinical Features

The hair loss in FPHL involves the same general areas of the scalp as in MPHL (Fig. 10.7) but the final extent of loss in the various regions of the scalp is less. Mild bitemporal recession, which in women implies finer and shorter hairs [52] versus balding as in MPHL, has been noted to occur in 60% [39] to 64% [32] of women and to increase with age [104]. Although it may be associated with the other areas of hair loss seen with FPHL, bitemporal recession may occur alone or in association with chronic telogen effluvium (CTE). There are two main ages of onset of FPHL, one in the immediate post-puberty period to the third decade, much like that of MPHL, and a second peak in the fifth and early sixth decade [62]. Women with early-onset FPHL are much more likely to have an associated hyperandrogenism and clear-cut AGA than those with late-onset FPHL. The late-onset FPHL often corresponds temporally to perimenopause or menopause but hormone replacement therapy with estrogen does not reverse this process. There is an age-related decrease in

Fig. 10.7  Regions of the scalp potentially involved in pattern hair loss. (F Frontal, M mid, T temporal, V vertex) (reprinted with permission from Olsen [63])

hair density [5, 9, 63, 69] that is always greater on the central scalp and that overlaps and undoubtedly contributes to the hair loss of late-onset FPHL. The hallmark of FPHL, as in MPHL, is an increase in miniaturized hair in the affected scalp. Two factors have been proposed to cause this miniaturization of terminal hairs: a shortening of anagen (which leads to shorter hairs and an increased percentage of hairs in telogen) and a smaller dermal papillae/hair matrix which leads to a transformation from terminal to vellus hair diameter. This is mirrored in the typical histopathological findings on scalp biopsies of an increase in telogen hairs and vellus-like hairs compared to normal [110]. The accompanying age-related decrease in hair diameter is not race specific [43, 98]. In women, as opposed to men, with pattern hair loss, this miniaturization process does not progress to baldness because all hairs in the affected areas of the central scalp are not equally affected and the miniaturization is not as profound. Early in the process of FPHL, there may be an increase in hair shedding which on clinical exam is manifest as a positive telogen hair pull in affected areas. However, over time, this hair shedding tends to stabilize and a hair

Female Pattern Hair Loss

Chapter 10

cially located miniaturized follicle. A mild perifollicular lymphohistiocytic infiltrate primarily around the upper follicle is common even in those without hair loss, but is increased in extent and degree in those with pattern hair loss. Concentric perifollicular fibrosis may be present. Sebaceous glands remain intact.

10.7

Fig. 10.8  Focal atrichia. Note the pencil eraser sized areas of hair loss

pull may not be positive even in the most profound examples of FPHL. This lack of shedding may be because of two factors. First, a lag phase at the end of telogen that delays the onset of a new anagen phase is seen in both male and female pattern hair loss [21, 37]. This lag phase would account for the affected follicles remaining empty for much longer than the usual telogen phase. Second, the decreased shedding could result from the overall decreased density of terminal hairs as it is only shedding of terminal hair that causes patient consternation and/or is assessed on the hair pull evaluation. This lag phase may be related to a specific clinical clue to the diagnosis of PHL, i.e., the presence of what Olsen has termed “focal atrichia” or small eraser-sized areas of baldness [36, 37, 59, 99] (Fig. 10.8). Olsen and Whiting have found this focal atrichia to be a relatively specific clinical finding in late versus early FPHL and to be histologically characterized by a decrease in density of both terminal hairs and follicular units (E.A. Olsen; unpublished information). A brown halo at the base of the affected follicles has been noted as a clinical clue to pattern hair loss (peripilar sign) in both men and women [25]. This may relate to the common histopathological finding of chronic inflammation in pattern hair loss and could represent post-inflammatory hyperpigmentation.

10.6

Histopathology

Both MPHL and FPHL have similar histopathologic findings [108, 110, 111]. There is a decrease in terminal hair in favor of vellus-like hair, a decrease in anagen hairs in favor of telogen hairs, and an increase in follicular stelae (the residual fibrous tract marking where former terminal hairs resided) ending in the superfi-

Differential Diagnosis

The primary differential diagnosis for FPHL is chronic telogen effluvium (CTE). Originally described by Whiting [109], CTE is defined here as chronic diffuse scalp hair shedding of greater than 6 months’ duration, often accompanied by bitemporal recession. Hair loss is usually not obvious to the evaluating physician but the hair pull is positive for telogen hairs in multiple areas of the scalp, including the occiput, as opposed to FPHL in which there should never be a positive hair pull from the occiput unless there is a superimposed telogen effluvium. The hair pull also excludes loose anagen syndrome in which multiple loose anagen hairs are generally seen and corroborated on microscopic exam. Screening by history and laboratory tests for other specific causes of hair loss are prerequisites and the diagnosis of CTE should exclude hair loss in those with known thyroid disease, connective tissue disease, obvious nutritional deficiencies or drugs known or suspected to cause hair loss. There is some thought that CTE can be definitively discriminated from FPHL by biopsy of the scalp and, indeed, there is a higher terminal/vellus hair ratio in CTE (>11:1) versus FPHL (2.2:1) [110]. However, in early FPHL, and in the elderly female patient who naturally has an increased percentage of age-related miniaturized hairs, this distinction may be difficult to make. Sinclair has noted that taking more than one scalp biopsy will increase the reliability of discriminating between FPHL and CTE [88]. Occasionally, alopecia areata can present without patches of hair loss but rather with a diffuse scalp hair loss. This hair loss is not usually limited to the top of the scalp and the hair pull is quite different from that seen in FPHL since both telogen and dystrophic anagen hairs are found in alopecia areata versus only telogen hairs in FPHL. Trichotillomania can rarely mimic FPHL since some women or girls with this psychological disorder may preferentially choose to pull out hair on the top of the scalp. However, even when the plucked hairs in the affected area have been allowed to partially regrow, the exceptionally short length of all hairs in the involved area, the normal diameter of the involved hairs and the high proportion of tapered tips of the short hairs signifying new synchronous anagen growth distinguish this

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clinically from FPHL. Trichotillomania also can be definitively discriminated from FPHL by scalp biopsy. One should also consider several cicatricial alopecias in the differential diagnosis for FPHL. In 2002, Zinkernagel and Trueb described 19 men and women with AGA that had “follicular keratosis,” and perifollicular erythema and obliteration of follicles in the distribution of hair loss [114]. On biopsy, there were typical histopathological features of AGA (miniaturization, replacement of terminal hair by fibrous tracts) along with a lichenoid and an isthmus/infundibular lymphohistiocytic infiltrate and follicular loss. This condition was called “fibrosing alopecia in a pattern distribution” (FAPD). Kossard later presented another cicatricial variant of hair loss, “frontal fibrosing alopecia,” occurring primarily in the same age group of Caucasian women, with the same perifollicular erythema and with the same histological findings of lichen planopilaris but with the hair loss limited to the frontal hair line [46]. Although frontal fibrosing alopecia has since been reported to occur in some cases with FAPD, clearly these conditions may occur independently and only FAPD presents any difficulties in distinguishing from FPHL. The clinical presentation of FAPD is very similar to what Olsen has called “cicatricial pattern hair loss” or CPHL [65]. In CPHL, also seen primarily in middleaged to older Caucasian women, there is a decrease in density on the top of the scalp in the distribution of a Ludwig pattern of FPHL plus/minus erythema but without any perifollicular papules or follicular accentuation as with FAPD (Fig. 10.9). The biopsy in CPHL is very different from FAPD and shows the typical miniaturization findings of FPHL but with an increase in fibrosis and a marked decrease in the expected number of hair follicles (normal being approximately 35 per 4-mm punch biopsy) [108, 111]. It is likely that CPHL represents an end stage of FPHL much like a Hamilton Norwood pattern VII represents an end stage of earlier patterns of MPHL. However, it is unclear why this degree of follicular drop-out should occur in only a subset of women with FPHL and how (or if) CPHL is related to FAPD. Lastly, in the discussion of the differential diagnosis of FPHL, one must also consider central centrifugal cicatricial alopecia (CCCA), an extremely common type of permanent hair loss in African-American women [68]. The hair loss in CCCA initially presents in the central scalp, spreads centrifugally and may potentially involve all but the “Hippocratic wreath” of hair always spared in MPHL. The hair loss in well developed CCCA is accompanied by clinically obvious atrophy and baldness versus the hair loss in FPHL which never leads to baldness, even with CPHL, and does not have an atrophic scalp. FPHL may be seen in African-American women but, when present, is usually mild in degree. Whether CCCA

 

Fig. 10.9  Severe female pattern hair loss with follicular dropout (“cicatricial pattern hair loss”)

represents the end result of severe FPHL in AfricanAmerican women, perhaps related to hair care practices unique to this population [65], remains to be explored. If that is the case, it would explain the much less common occurrence of “typical” FPHL in African-American women compared to women of European descent.

10.8

Evaluation

The primary reasons for the evaluation of women with the typical clinical picture of FPHL are to: (1) rule out close mimickers of FPHL not otherwise possible by clini­cal exam alone; (2) determine if there are treatable factors that may negatively impact on the therapeutic interventions for FPHL or in themselves are causing hair loss; and (3) determine the potential reversibility of the hair loss process. A recent consensus publication on this topic by experts in the field offers a complete overview of this topic [69].

Female Pattern Hair Loss

A history should include the time of onset of hair loss, the location of the hair loss, whether increased shedding was present at onset and continues, and the relationship of hair loss to significant life events, illness, surgery, changes in diet or weight loss or new medications within 6 months prior to the hair loss onset. Questions should include whether the menses in the third to fourth decades were regular or required oral contraceptive agents to regulate, whether the woman was able to conceive without artificial stimulation, whether hirsutism is present and being treated and, if so, when it started and whether a family history of the same is present. It is important to know if the menses are now regular, changing or absent, and whether any supplemental hormones have been stopped or started in the recent past. Physical exam should include the scalp with attention particularly to whether hair loss excludes the occiput, which is typical of FPHL: this can be ascertained by comparing the part width in the occiput with that on the top of the scalp [60]. Notation should be made as to any patches of hair loss, focal atrichia, broken hairs, general scalp erythema or atrophy or perifollicular erythema. Hair pull should be performed on the top, sides and occiput and the proximal ends of any hairs evaluated microscopically to ensure only telogen hairs. Signs of hirsutism should be looked for and nails should be evaluated for pits. A scalp biopsy should be done from the involved area when the diagnosis is in doubt or to determine the potential reversibility of the hair loss. Screening blood work should always include at least a thyroid-stimulating hormone (TSH) if not also a free thyroid hormone level (T4): any telogen effluvium related to thyroid deficiency or excess is imminently treatable and the related hair loss reversible. It is probably also wise to check the patient’s iron status given that there is some question about the relationship of iron deficiency to FPHL [96] and a suggestion that the response to cyproterone acetate and ethinyl estradiol for FPHL is diminished in the face of uncorrected iron deficiency [81]. Moreover, iron deficiency anemia can be the sign of a serious underlying medical problem. To screen for iron deficiency, a serum ferritin is a reasonable test of iron stores but because it is an acute phase reactant and will be elevated in the face of acute inflammation for example, a sedimentation rate should be done along with the ferritin. If the ferritin is normal in the face of an elevated sedimentation rate, one must do additional tests [iron and total iron binding capacity (TIBC)] to confirm that iron stores are normal. A complete blood count (CBC) should be done to rule out anemia including iron deficiency anemia. Iron deficiency should be corrected with oral supplements to a ferritin level of at least 40 ng/ml, perhaps higher.

Chapter 10

Although there are some data to support that MPHL, especially vertex hair loss, is related to coronary artery disease in men [69], the data regarding this in women with FPHL are scanty. In a study of 106 women 100 mg per day are primarily on cohorts of fewer than ten women [10, 82]. However, there is one 12-month trial of spironolactone 200 mg per day in 40 women with FPHL with documented efficacy in 45% of women [89]. Despite a lack of further documentation of efficacy, spironolactone is used regularly in the

Female Pattern Hair Loss

treatment of women with FPHL, particularly in those women with documented hyperandrogenism. Hyperkalemia ia a potential side-effects of spironolactone related to its aldosterone antagonist/potassiumsparing effect on the kidney, and potassium levels should be checked after starting the drug. Since spironolactone may cause breast tenderness, irregular menses and mood swings,it is wise to put women of child-bearing potential on an oral contraceptive agent prior to beginning spironolactone. There is one oral contraceptive agent, Yasmin®, whose 3 mg of progesterone (drospirenone) has an inherent spironolactone-like effect equivalent to 25 mg of spironolactone, not enough by itself to expect to see an effect on FPHL [112].

10.9.4 Flutamide Flutamide, or its metabolite 2-hydroxy-flutamide, is a non-steroidal pure antiandrogen with no intrinsic androgenic activity. It inhibits the binding of testosterone to the androgen receptor, the negative feedback of gonadal steroids at the hypothalamic–pituitary level, and adrenal 17,20-desmolase, with a resulting decrease in DHEA and DHEAS [22, 86]. Excretion is primarily renal [94]. Flutamide has been evaluated only in women with hair loss who also have hyperandrogenism. Carmina and Lobo evaluated 250 mg of flutamide daily versus cyproterone acetate versus finasteride versus observation alone in 48 women (12 women in each group) with FPHL and documented hyperandrogenism [14]. The flutamide group had a statistically significant improvement in the Ludwig score and in the investigator assessment over the observation group. Extrapolation from anecdotal reports in women with hirsutism who also had hair loss showed that 250 mg of flutamide twice daily in combination with an oral contraceptive agent had cosmetically acceptable growth in six out of seven women and may have efficacy in alopecia beyond that of spironolactone [23]. Its primary side-effects are gastrointestinal including diarrhea although the use of flutamide is limited by its known hepatotoxicity, which can be fatal [34].

10.9.5 Cyproterone Acetate Cyproterone acetate blocks DHT-androgen receptor binding and, given its steroid structure, has progestogen and antigonadotropic properties [40]. In women of child-bearing potential, estrogens are usually given with cyproterone acetate to reinforce the latter effect and to ensure regular menses. Two combinations of cypro­ terone acetate with 50 µg ethinyl estradiol are utilized

Chapter 10

for their antiandrogen effect in premenopausal women: (1) 100 mg along with estrogen on days 5–15 and estrogen alone on days 16–25 (cyclical antiandrogen therapy or CAT) for hirsutism or (2) 2 mg in combination with estrogen on days 5–25 (Diane®). In postmenopausal women, 50 mg of cyproterone acetate daily may be used alone. Potential side-effects are dose related and include menstrual irregularity, weight gain, breast tenderness, decreased libido, depression, and nausea [103]. There have been few controlled clinical trials of cyproterone acetate in FPHL. In one study 20 female patients with AGA were treated for 1 year with daily 50 µg ethinyl estradiol and 2 mg cyproterone acetate (Diane®) plus an additional 20 mg cyproterone acetate on days 5–20 of the menses and were compared to 10 untreated control patients with AGA for 1 year [76]. Trichogram results as well as hair diameter on the fronto-cranial and temporal scalp were assessed. There was a statistically significant increase in the anagen/telogen ratio but no decrease in vellus hairs on the fronto-cranial scalp in the cyproterone acetate group compared to controls. In another study, 40 patients with FPHL were treated with cyproterone acetate for 12 months, 22 postmenopausal women with 50 mg cyproterone acetate daily, and 18 premenopausal women with 100 mg cyproterone acetate daily for 10 days each month along with a combination oral contraceptive pill [89]. Of 40 women, 17 (42.5%) had a positive response documented photographically. These results were almost identical to the comparative group of 40 patients treated with spironolactone. A 48-week trial conducted by Vexiau et al. included equal numbers of women (33 each group) with female AGA treated with 52 mg per day of cyproterone acetate plus ethinyl estradiol 35  µg for 20 of every 28 days or 2% topi­cal minoxidil solution 1 ml bid plus combined oral contraceptive use [105]. Between baseline and 12 months, there was no significant difference in the mean number of target area hairs in the cyproterone group but an increase in the minoxidil group. There was no difference in the results with cyproterone acetate and FPHL with the presence or absence of other signs of hirsutism. Dawber et al. has suggested that there is a minimally effective dose of cyproterone acetate, as 24 out of 29 women had improvement in FPHL when treated with 50 µg ethinyl estradiol and 200 mg cyproterone acetate daily but 14 of 17 who remained on Diane® (2 mg cyproterone acetate) failed to maintain that response [24]. Mortimer et al. reported a positive response to treatment with CAT in three women with FPHL [55]. Hammerstein treated patients with hirsutism and various other potentially androgen-related effects with cyproterone acetate, and although the hirsutism, acne, and seborrhea responded to the drug, the AGA did not [40]. Similarly, Ekoe found that 6 out of 11 patients with hair loss and hirsutism treated with cyproterone acetate 100

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mg on days 5–14 and ethinyl estradiol on days 5–25 did not even have stabilization of hair loss [28].

10.9.6 Other Antiandrogens Cimetidine is an H2 antihistamine that inhibits DHT binding. One uncontrolled study of 300 mg five times a day suggests some efficacy in FPHL [2].

10.9.7 5α-Reductase Inhibitors

10

As previously noted, in a large controlled multicenter trial of postmenopausal women with FPHL, the results with finasteride 1 mg were not found to be significantly different from placebo at the end of one year [77]. However, there were individual subjects in this trial who did have hair growth on finasteride 1 mg and there have since been anecdotal reports of finasteride being effective in postmenopausal women without hyperandrogenism at 1 or 2.5 mg doses [92, 97, 102] and in women with hyperandrogenism at 2.5 mg [87]. There are no placebo or active controlled studies of finasteride in premenopausal women with early-onset FPHL but there is now a controlled open label study of 37 premenopausal women with FPHL and no hyperandrogenemia or signs of hyperandrogenism [42]. These women were given 2.5 mg of finasteride daily in conjunction with the oral contraceptive Yasmin®. Efficacy was judged based on global photographs and the deLachariere hair part density scale. At the conclusion of 12 study months, 60% of the women had increased hair growth as documented by global photographs (11 of 37 moderate or greater hair growth) and 12 of 37 (32%) had an increase in hair density. There were no adverse reactions. Camacho has reported the effectiveness of finasteride 2.5 mg in 41 women with FPHL and SAHA (seborrhea, acne, hirsutism, and acne) [11]. Finasteride, a type II 5α-reductase inhibitor, has been shown in men to decrease serum DHT by 67% [80] with 1 mg and 68.5% with 5 mg [27] and scalp DHT by 64.1% with 1 mg and 69% with 5 mg [27]. Based on the lack of a significant difference in DHT suppression between 1 and 5 mg of finasteride, there would appear to be no advantage to taking 1 versus 2.5 mg per day of finasteride as has been done in some reports of women with FPHL. Dutasteride is a dual type I and type II 5α-reductase inhibitor currently approved in a 0.5-mg dose form for prostatic hyperplasia. In a comparative study of men with MPHL, serum DHT was suppressed by 92% versus 73% and scalp DHT by 51% versus 41% in men treated with 0.5 mg dutasteride versus 5 mg finasteride respectively [70]. Suppression of DHT was correlated with hair count in men with MPHL. Dutasteride has a

 

much longer half-life than finasteride (4 weeks versus 6–8 hours) with prolonged suppression of DHT and has not been subjected to any clinical trials in women. However, Olszewska reported on one postmenopausal woman with FPHL who responded to dutasteride and not finasteride [72]. Women of child-bearing potential should be on an effective form of contraception prior to beginning any 5α-reductase inhibitor since 5α-reductase inhibitors have the potential to cause feminization of a male fetus: an oral contraceptive pill is the contraceptive of choice for the additional reason that it will decrease production of circulating androgens. Given its longer half-life, dutasteride should not be taken by women of child-bearing potential.

10.9.8 Estrogens Estrogens given systemically increase the production of SHBG leading to a decrease in free testosterone. Topical 0.025% 17α-estradiol preparation appeared to stabilize hair loss when applied for 6 months by seven women with AGA and/or increased telogen hair shedding compared to two female controls [73]. Interestingly, hair loss has not been one of the common side-effects reported with systemic aromatase inhibitors [90].

10.9.9 Estrogen Receptor Antagonist Largely based on the anagen-promoting activity of an ER antagonist in mice [58], a proof of concept study was done in 70 postmenopausal women with Ludwig I or II FPHL treated with either fulvostatin (an estrogen receptor antagonist) or placebo for 16 weeks [33]. There was no statistically significant difference between groups in hair density, cumulative hair thickness or growth rate. In clinical practice, hair loss or growth has not been a common side-effect of estrogen receptor inhibitors [35].

10.9.10 Melatonin Melatonin has been shown to promote anagen induction in animals. In a double-blind randomized placebo-controlled study, women aged 20–70 with diffuse alopecia (n= 28) or AGA (n= 12) were treated with 1 ml daily of 0.1% melatonin–alcohol solution versus vehicle topically for 6 months. Efficacy was determined by trichograms in the frontal and occipital areas [30]. At the conclusion of the study of women with FPHL, there was a statistically significant increase from baseline in anagen hairs in the occiput in the topical melatonin group (mean 76.3 to 85.2 hairs) compared to placebo (mean 78 to 82 hairs) but no difference from placebo in the frontal area.

Female Pattern Hair Loss

10.10 Surgical Treatment Hair transplants may be extremely useful in FPHL, the limitations being adequate donor hair, reasonable expectations, and cost. Before the development of follicular unit transplanting and slit grafting, donor tissue was removed by round trephines and the grafts were placed into holes made by marginally smaller trephines. Since the recipient site in FPHL was not bald but only less dense than normal, this led to the unnecessary removal of some viable terminal hair when preparing the recipient hole. The advent of follicular unit transplants, in which 1- to 2-unit grafts are placed into the recipient area by a hypodermic needle hole or slit made by a scalpel, has eliminated this. Grafts are generated from elliptical donor strip harvesting the same in women as in men, except that the donor area may be more restricted in women than men: the temporal and inferior parietal/occipital areas are not used for donor areas in women in order to prevent future limitations in hair styles [100]. In the focal atrichia areas, Unger either places larger follicular units or removes the bald skin by trephine and places a larger graft into these new recipient sites. Realistic goals for transplant should established: an increase in hair density in strategic areas seems feasible in most women with further goals dependent on the donor site and number of sessions. Postoperatively, there may be a temporary loss of hair in both the donor and recipient areas. This effect may be mitigated by the use of topical minoxidil [4].

Summary for the Clinician Female pattern hair loss is a common condition with two primary ages of onset: early, which overlaps with male pattern hair loss (MPHL), and late, which presents in the early fifth decade and overlaps with menopause. Most patients with FPHL do not have documented signs of hyperandrogenism or hyperandrogenemia. The response to antiandrogens and 5α-reductase inhibitors highlight the issues surrounding the etiology of FPHL, which is still unclear for all patients. Finasteride, a 5α-reductase inhibitor, was shown not to be effective in a placebo-controlled trial in postmenopausal women with FPHL but there is encouraging information about its efficacy in early-onset FPHL and information from non-placebo-controlled studies that it may be useful in some postmenopausal women as well. Topical minoxidil remains a mainstay of treatment and hair transplants now offer a viable alternative effective treatment for many women with FPHL.

Chapter 10

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Schmidt HB, Lindmaier A, Trenz A, et al (1991) Hormone studies in females with androgenic hairloss. Gynecol Obstet Invest; 31: 235-239 85. Schweikert HU, Wilson JD (1974) Regulation of human hair growth by steroid hormones. I. Testosterone metabolism in isolated hairs. J Clin Endocrinol Metab 38: 811-819 86. Sciarra F, Toscano V, Concolino G, et al (1990) Antiandrogens: clinical applications. J Steroid Biochem Mol Biol; 37: 349-362 87. Shum KW, Cullen DR, Messenger AG (2002) Hair loss in women with hyperandrogenism: four cases responding to finasteride. J Am Acad Dermatol; 47: 733-739 88. Sinclair R (2004) The reliability of horizontally sectioned scalp biopsies in the diagnosis of chronic diffuse telogen hair loss in women. J Am Acad Dermatol; 51: 189-199 89. Sinclair R, Wewerinke M, Jolley D (2005) Treatment of female pattern hair loss with oral antiandrogens. Br J Dermatol; 152: 466-473 90. Smith IE, Dowsett M (2003) Aromatase inhibitors in breast cancer. N Engl J Med; 348: 2431-2442 91. Smith MA, Wells RS (1964) Male-type alopecia, alopecia areata and normal hair in women: family histories. Arch Dermatol; 89: 95-98 92. Thai K-E, Sinclair RD (2002) Finasteride for female androgenetic alopecia. Br J Dermatol; 147: 808-840 93. Thornton MJ (2002) The biological actions of estrogens on skin. Exp Dermatol; 11: 487-502 94. Tindll DJ, Chang CH, Lobl TJ, et al (1984) Androgen antagonists in androgen target tissues. Pharmacol Ther; 24: 367-400 95. Tremblay RR (1986) Treatment of hirsutism with spironolactone. Clin Endocrinol Metab; 15: 363-371 96. Trost LB, Bergfeld WF, Calgeras E (2006) The diagnosis and treatment of iron deficiency and its potential relationship to hair loss. J Am Acad Dermatol; 54: 824-844 97. Trueb RM (2004) Finasteride treatment of patterned hair loss in normoandrogenic postmenopausal women. Dermatology; 209: 202-207 98. Ueki R, Tsuboi R, Inaba Y, et al (2003) Phototrichogram analysis of Japanese female subjects with chronic diffuse hair loss. J Investig Dermatol Symp Proc; 8: 116-120 99. Unger WP, Hair transplantation in females. In: Unger WP (ed) (1988) Hair Transplantation. Dekker, New York, pp. 295-300 100. Unger WP, Unger RH (2003) Hair transplanting: an important but often forgotten treatment for female pattern hair loss. J Am Acad Dermatol; 49: 853-860

  101. Uno H, Cappas A, Schlagel C (1985) Cyclic dynamics of hair follicles and the effect of minoxidil on the bald scalps of stumptailed macaques. Am J Dermatopathol; 7: 283-297 102. Valsecchi R, Leghissa P, Riva M (2004) Female androgenetic alopecia treated by finasteride: a case forward. Acta Derm Venereol; 84: 488-489 103. Vanwayjen RG, Van den Ende A (1995) Experience in the long term treatment of patients with hirsutism and/ or acne with cyproterone acetate containing preparations: efficacy, metabolic and endocrine effects. Exp Clin Endocrinol Diabetes; 103: 241-251 104. Venning VA, Dawber RPR (1988) Patterned androgenic alopecia in women. J Am Acad Dermatol; 18: 1073-1077 105. Vexiau P, Chaspoux C, Boudou P, et al (2002) Effects of minoxidil 2% vs cyproterone acetate treatment on female androgenetic alopecia: a controlled, 12-month randomized trial. Br J Dermatol; 146: 992-999 106. Vierhapper H, Nowotny P, Maier H, et al (2001) Production rates of dihydrotestosterone in healthy men and women and in men with male pattern baldness: determination by stable isotope/dilution and mass spectrome­ try. J Clin Endocrinol Metab; 86: 5752-5764 107. Vierhapper H, Maier H, Nowotny P, et al (2003) Production rates of testosterone and dihydrotestosterone in female pattern hair loss. Metabolism; 52: 927-929 108. Whiting DA (1993) The diagnostic and predictive value of horizontal sections of scalp biopsies in male pattern androgenetic alopecia. J Am Acad Dermatol; 28: 755-763 109. Whiting DA (1996) Chronic telogen effluvium: increased scalp hair shedding in middle-aged women. J Am Acad Dermatol; 35: 899-906 110. Whiting DA (1998) Scalp biopsy as a diagnostic and prognostic tool in androgenetic alopecia. Dermatol Ther; 8: 24-33 111. Whiting DA, Waldstreicher J, Sanchez M, et al (1999) Measuring reversal of hair miniaturization in androgenetic alopecia by follicular counts in horizontal sections of serial scalp biopsies. Results of finasteride 1 mg treatment of men and postmenopausal women. J Invest Dermatol Symp Proc; 4: 282-284 112. Yasmin (2007) Physician’s Desk reference; 61: 796-803 113. Zajac JD (2003) Women, androgens and skin (abstract). Exp Dermatol; 12: 224 114. Zinkernagel MS, Trueb RN (2002) Fibrosing alopecia in a pattern distribution: patterned lichen planopilaris or androgenetic alopecia with a lichenoid tissue reaction pattern? Arch Dermatol; 135: 205-211

Chapter 11

Primary Cicatricial Alopecia Elizabeth Katrina Ross, Jerry Shapiro

 

 

11

6

Synonyms Primary scarring alopecia



Key Features

• Group of largely uncommon disorders. • Result from primary destruction of the hair follicle, often affecting the scalp. • Cause and pathogenesis incompletely understood. • Clinical hallmark loss of follicular ostia. • Classified provisionally by primary inflammatory

• Prompt intervention key to thwarting continued hair loss. • In general, formal, controlled studies on treatment are lacking.

cell infiltrate.

 

Contents 11.1 11.2 11.3 11.3.1 11.3.1.1 11.3.2 11.3.2.1 11.3.2.2 11.3.2.3 11.3.2.4 11.3.2.5 11.3.2.6 11.3.2.7 11.3.3 11.3.3.1 11.3.3.2 11.3.3.3 11.3.3.4 11.3.3.5 11.3.3.6 11.3.3.7

Approach to the Patient with Cicatricial Alopecia  . . . . . . . . . . . . . . Classification   . . . . . . . . . . . . . . . . . . . . . . . . Lymphocytic Disorders  . . . . . . . . . . . . . . . Lichen Planopilaris  . . . . . . . . . . . . . . . . . . . Classic Lichen Planopilaris  . . . . . . . . . . . . Frontal Fibrosing Alopecia  . . . . . . . . . . . . . History  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology  . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis  . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features  . . . . . . . . . . . . . . . . . . . . . Pathology  . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis  . . . . . . . . . . . . . . . . . Treatment  . . . . . . . . . . . . . . . . . . . . . . . . . . . Piccardi–Lassueur–Graham Little Syndrome  . . . . . . . . . . . . . . . . . . . . . . . . . . . History  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology  . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis  . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features  . . . . . . . . . . . . . . . . . . . . . Pathology  . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis  . . . . . . . . . . . . . . . . . Treatment  . . . . . . . . . . . . . . . . . . . . . . . . . . .

  189   189   189   189   190   193   193   193   193   193   194   194   194   195   195   195   195   195   195   195   195

11.3.4 11.3.5 11.3.5.1 11.3.5.2 11.3.5.3 11.3.5.4 11.3.5.5 11.3.5.6 11.3.5.7 11.3.6 11.3.6.1 11.3.6.2 11.3.6.3 11.3.6.4 11.3.6.5 11.3.6.6 11.3.6.7 11.3.7 11.3.7.1 11.3.7.2 11.3.7.3 11.3.7.4

Fibrosing Alopecia in a Pattern Distribution  . . . . . . . . . . . . . . . . . . . . . . . . .   195 Pseudopelade of Brocq  . . . . . . . . . . . . . . . .   196 History  . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   196 Epidemiology  . . . . . . . . . . . . . . . . . . . . . . . .   196 Pathogenesis  . . . . . . . . . . . . . . . . . . . . . . . . .   197 Clinical Features  . . . . . . . . . . . . . . . . . . . . .   197 Pathology  . . . . . . . . . . . . . . . . . . . . . . . . . . .   198 Differential Diagnosis  . . . . . . . . . . . . . . . . .   198 Treatment  . . . . . . . . . . . . . . . . . . . . . . . . . . .   198 Central Centrifugal Cicatricial Alopecia  .   198 History  . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   198 Epidemiology  . . . . . . . . . . . . . . . . . . . . . . . .   199 Pathogenesis  . . . . . . . . . . . . . . . . . . . . . . . . .   199 Clinical Features  . . . . . . . . . . . . . . . . . . . . .   199 Pathology  . . . . . . . . . . . . . . . . . . . . . . . . . . .   199 Differential Diagnosis  . . . . . . . . . . . . . . . . .   199 Treatment  . . . . . . . . . . . . . . . . . . . . . . . . . . .   200 Alopecia Mucinosa  . . . . . . . . . . . . . . . . . . .   200 History  . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   200 Epidemiology  . . . . . . . . . . . . . . . . . . . . . . . .   200 Pathogenesis  . . . . . . . . . . . . . . . . . . . . . . . . .   200 Clinical Features  . . . . . . . . . . . . . . . . . . . . .   201

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11

11.3.8.1 11.3.8.2 11.3.8.3 11.3.8.4 11.3.8.5 11.3.8.6 11.3.8.7 11.3.9 11.3.9.1 11.3.9.2 11.3.9.3 11.3.9.4 11.3.9.5 11.3.9.6 11.3.9.7 11.4 11.4.1 11.4.1.1 11.4.1.2 11.4.1.3 11.4.1.4 11.4.1.5 11.4.1.6 11.4.1.7 11.4.2 11.4.2.1 11.4.2.2 11.4.2.3 11.4.2.4 11.4.2.5

Differential Diagnosis  . . . . . . . . . . . . . . . . . Pathology  . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment  . . . . . . . . . . . . . . . . . . . . . . . . . . . Keratosis Follicularis Spinulosa Decalvans (KFSD)  . . . . . . . . . . . . . . . . . . . . History  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology  . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis  . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features  . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis  . . . . . . . . . . . . . . . . . Pathology  . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment  . . . . . . . . . . . . . . . . . . . . . . . . . . . Discoid Lupus Erythematosus  . . . . . . . . . . History  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology  . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis  . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features   . . . . . . . . . . . . . . . . . . . . . Pathology  . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis  . . . . . . . . . . . . . . . . . Treatment  . . . . . . . . . . . . . . . . . . . . . . . . . . . Neutrophilic Disorders  . . . . . . . . . . . . . . . . Folliculitis Decalvans  . . . . . . . . . . . . . . . . . History  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology  . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis  . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features  . . . . . . . . . . . . . . . . . . . . . Pathology  . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis  . . . . . . . . . . . . . . . . . Treatment  . . . . . . . . . . . . . . . . . . . . . . . . . . . Perifolliculitis Abscedens et Suffodiens  . . History  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology  . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis  . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features  . . . . . . . . . . . . . . . . . . . . . Pathology  . . . . . . . . . . . . . . . . . . . . . . . . . . .

  201   201   202   202   202   203   203   203   204   204   204   205   205   205   205   205   206   207   207   208   208   208   208   208   208   208   209   209   211   211   211   211   212   213

The primary cicatricial alopecias are a largely uncommon group of disorders characterized by permanent destruction of the hair follicle – often involving the scalp alone – with relative sparing of the nonfollicular structures in the skin. Hallmark features are absent follicular ostia on exam and scarred fibrous tracts that mark extinct follicles on pathology. Although several types of primary cicatricial alopecia have been recognized since the nineteenth century, little is known about the cause and pathogenesis of individual disease. All presumably result from irreversible injury to the stem-cell-rich bulge area, which is required for cyclic regeneration of the lower follicle [115]. Indeed, in all forms of primary cicatricial alopecia this portion of the follicle is generally affected. In contrast, when the

  11.4.2.6 11.4.2.7 11.5 11.5.1 11.5.1.1 11.5.1.2 11.5.1.3 11.5.1.4 11.5.1.5 11.5.1.6 11.5.1.7 11.5.2 11.5.2.1 11.5.2.2 11.5.2.3 11.5.2.4 11.5.2.5 11.5.2.6 11.5.2.7 11.5.3 11.5.3.1 11.5.3.2 11.5.3.3 11.5.3.4 11.5.3.5 11.5.3.6 11.5.3.7 11.6 11.7

Differential Diagnosis  . . . . . . . . . . . . . . . . . Treatment  . . . . . . . . . . . . . . . . . . . . . . . . . . . Mixed Cicatricial Alopecia  . . . . . . . . . . . . . Acne Keloidalis  . . . . . . . . . . . . . . . . . . . . . . History  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology  . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis  . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features  . . . . . . . . . . . . . . . . . . . . . Pathology  . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis  . . . . . . . . . . . . . . . . . Treatment  . . . . . . . . . . . . . . . . . . . . . . . . . . . Acne Necrotica   . . . . . . . . . . . . . . . . . . . . . . History  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology  . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis  . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features  . . . . . . . . . . . . . . . . . . . . . Pathology  . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis  . . . . . . . . . . . . . . . . . Treatment  . . . . . . . . . . . . . . . . . . . . . . . . . . . Erosive Pustular Dermatosis  . . . . . . . . . . . History  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology  . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis  . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features  . . . . . . . . . . . . . . . . . . . . . Pathology  . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis  . . . . . . . . . . . . . . . . . Treatment  . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgical Correction of Burnt-Out Cicatricial Alopecia  . . . . . . . . . . . . . . . . . . . General Measures for Management of Cicatricial Alopecia  . . . . . . . . . . . . . . . . Summary for the Clinician  . . . . . . . . . . . . .

  213   213   214   214   214   214   214   215   215   215   215   216   217   217   217   217   217   217   217   218   218   218   218   218   219   219   219   219   219   220

References   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   220

lower, nonpermanent portion of the follicle is involved, as in alopecia areata, these critical cells are left unperturbed and the potential to regrow hair remains intact. Known aspects of evolving disease in humans and rodent models of primary cicatricial alopecia (for which there is no human correlate) suggest that primary follicular destruction can result from a variety of means, including: (1) sebaceous gland pathology, (2) outer root sheath compromise, and possibly even (3) primary follicular stem cell failure [88, 145, 162]. In some conditions, a genetic propensity (e.g., in keratosis follicularis spinulosa decalvans) and exogenous triggers (e.g., ultraviolet light in discoid lupus erythematosus, medications in lichen planopilaris and acne keloidalis, and possibly Staphylococcus aureus in folliculitis decalvans) are pathoge-

Primary Cicatricial Alopecia

netic factors. Now in the early twenty-first century, a concerted effort between bench researchers, clinicians, and pathologists is needed to further our understanding about this diverse, intriguing group of conditions.

11.1

Approach to the Patient with Cicatricial Alopecia

Prompt diagnosis and treatment of active disease to halt further hair loss is the goal. Clinical diagnosis of primary cicatricial alopecia should be confirmed by histopathology. A single 4-mm punch biopsy sample is recommended, taking care to choose a biopsy site with clinically representative active disease which is usually

Table 11.1  Working classification of primary cicatricial alopecias based on predominant inflammatory cell involved a Lymphocytic

Lichen planopilaris – – – –

Sparse, curly, and fair hair Classic variant Frontal fibrosing alopecia Piccardi–Lassueur–Graham Little syndrome – Fibrosing alopecia in a pattern distribution Pseudopelade of Brocq

Chapter 11

at the advancing, hair-bearing edge of an area of alopecia. Symptoms, inflammatory stigmata, and a positive pull test are helpful signs. Transverse sectioning of the biopsy specimen is conventionally advocated to ensure that all follicles are assessed at multiple planes; however, loss of critical diagnostic features in the epidermis, superficial dermis, and panniculus with this mode can impair interpretation [49, 69]. Obtaining a second specimen for vertical sectioning can improve diagnostic yield, but may still not allow distinction among predominantly lymphocytic or neutrophilic inflammation [48, 111]. The authors use this dual approach when faced with clinically puzzling cases and when discoid lupus erythematosus is considered. The specimen to be sectioned vertically is bisected, with half sent for hematoxylin-eosin staining and the other for direct immunofluorescence. Elastin stains can be used in more advanced disease to help distinguish between the more common lymphocytic predominant disorders (which often overlap both clinically and histopathologically) based on different patterns of scar formation [47]. Once the diagnosis is established, active disease must be treated immediately to thwart further hair loss. Although hampered in large part by the lack of formal, controlled studies, there are ample empiric data in most conditions to devise a tiered treatment plan. Flexibility is key. In some, the hair loss continues despite these measures, and cosmetic aids and supportive care are what are needed most.

11.2

Classification

Central centrifugal cicatricial alopecia Alopecia mucinosa Keratosis pilaris spinulosa decalvans/ Folliculitis spinulosa decalvans Discoid lupus erythematosus Neutrophilic

Folliculitis decalvans Perifolliculitis capitis abscedens et suffodiens

Mixed

Acne keloidalis Acne necrotica Erosive pustular dermatosis of the scalp

a

 Revised from NAHRS classification scheme, J Am Acad Dermatol 2003;48:103-10 [123]. Entities in italics may not be appropriately classified, distinct, or clearly primary in nature. See text for details.

A standardized classification scheme was adopted by the North American Hair Research Society in 2001 as a fulcrum for further discussion, debate, and research [123]. It is based on the primary inflammatory cell involved in active disease (lymphocytic, neutrophilic, or mixed) (Table 11.1). Modification is expected as advances occur. The chapter will address the entities listed in Table 11.1 in the order in which they appear.

11.3

Lymphocytic Disorders

11.3.1 Lichen Planopilaris Lichen planopilaris is a follicular form of lichen planus. Three clinical variants result in cicatricial alopecia: (1) classic lichen planopilaris; (2) frontal fibrosing alopecia; and (3) Piccardi-Lassueur-Graham Little syndrome.

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Elizabeth Katrina Ross, Jerry Shapiro

11.3.1.1  

 

Classic Lichen Planopilaris

6

Synonyms follicular lichen planus



Key Features

• Adults of all races affected, with female predominance. • Intensely pruritic. • White to ivory colored, depressed, reticulate or po-

lygonal-shaped alopecic plaques with perifollicular hyperkeratosis and variable erythema at the hairbearing margin. Positive pull test for anagen hairs when active. Lichen planus exists elsewhere in some. On histopathology, lichenoid interface dermatitis of the upper follicle associated with vacuolar change, apoptotic keratinocytes, hyperkeratosis, and hypergranulosis.

• • • 11  

11.3.1.1.1 History In 1895, Pringle presented a case of lichen planus associated with “lichen pilaris” of the neck, later commenting on other cases of folliculocentric lichen planus, some of which were associated with patchy alopecia of the scalp [139].

 

11.3.1.1.2 Epidemiology Classic lichen planopilaris is largely seen in adults, about twice as often in females based on most reports [34, 112, 166, 176]. Onset usually occurs between the ages of 25 and 70 years, typically in the mid-40s to early 50s. Children are less commonly affected. All races are susceptible.

11.3.1.1.3 Pathogenesis Lichen planopilaris is a T-cell disorder that involves the upper follicle, with an increased CD8:CD4 ratio and a marked diminishment of Ki-67-staining proliferative cells in the bulge, compared to normal follicles [112]. Certain drugs are known to trigger disease (e.g., gold and quinacrine hydrochloride), but in most cases the cause is unknown [145].

11.3.1.1.4 Clinical Features Intense pruritus and increased hair shedding are common presenting complaints [34, 110, 145]. Pain, burning, and scalp tenderness may also be experienced. The central scalp is a common target. Characteristically, perifollicular hyperkeratosis with variable erythema is seen at the hair-bearing margin of ivory-white atrophic reticulate or polygonal alopecic plaques (Fig.  11.1a,b). Features of nonfollicular lichen planus are usually absent. In early disease, little to no associated alopecia may be found. A positive pull test for anagen hairs at sites of

Fig. 11.1a–e  Classic lichen planopilaris. a Perifollicular scale and erythema at the margin of scarred alopecic areas. b Dermoscopy at 16× magnification showing perifollicular scale

Primary Cicatricial Alopecia

Chapter 11

Fig. 11.1a–e   (continued) c Overview showing extensive central scarring. d Histopathology at 40× magnification showing periinfundibular lichenoid interface changes. e Treatment algorithm

perifollicular inflammation may be the only indicator of active disease. The hair loss that follows can be limited or extensive (Fig. 11.1c). Remaining interspersed hairs can impart remarkable camouflage in some. Uncom-

monly, near-complete hair loss can develop. In general, the course of disease is indolent, with episodic bursts of activity.

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Nonscalp lichen planus develops in 50% of individ­ uals, often after the onset of scalp disease, according to one study [110]. When the form is lichen planopilaris or bullous, fulminant scalp disease may be seen [145]. Androgenetic alopecia frequently coexists (28%) [166]. An ulcerative variant of scalp lichen planopilaris occurs rarely; although linked to hepatitis C in one case the significance of this association is unknown [24].

11.3.1.1.5 Pathology

11

In early disease, a lymphocytic lichenoid interface dermatitis is seen to affect the infundibulum and isthmus, in association with vacuolar alteration, scattered dyskeratotic and necrotic keratinocytes in the basal layer, and colloid bodies in the adventitial dermis [5, 110, 112, 156] (Fig. 11.1d). This is accompanied by infundibular hyperkeratosis and hypergranulosis and atrophic or absent sebaceous glands. The adjacent epidermis may show features of typical lichen planus. With progression, the lichenoid infiltrate is displaced peripherally by lamellar fibroplasia that is seen to surround an atrophic, “squamatized” follicular epithelium. Follicular destruction follows, marked initially by foreign-body hair shaft granulomas, and then by longitudinal fibrotic tracts at the sites of extinct follicles – hallmark features seen in most of the primary cicatricial alopecias. Direct immunofluorescence, when positive, usually shows patchy deposition of fibrinogen and globular IgM along the follicular basement membrane zone. IgA is seen less commonly. In advanced disease, the elastin staining pattern reveals a superficial wedge-shaped scar associated with loss of the upper follicular elastic sheath [47].

11.3.1.1.6 Differential Diagnosis In its characteristic form, classic lichen planopilaris is distinctive. Problems differentiating lichen planopilaris from other entities arise when the condition is subacute or burnt out, in which case it most closely resembles pseudopelade of Brocq. Distinction between these two entities can be difficult and fuels the debate about their interrelationship, as will be discussed in Sect. 11.3.5.1.

11.3.1.1.7 General Treatment Measures Management of active primary cicatricial alopecia depends on several variables including diagnosis, age, symptom severity, extent, and patient preference. In general, local disease (6 months with unexplored or unknown etiologies.

• •

• Management of diffuse hair loss depends on the

cause and underlying pathomechanism in its relation to the hair growth cycle. Once the diagnosis is established, treatment appropriate for that diagnosis is likely to control the hair loss. Chronic telogen effluvium of unknown origin can be satisfactorily handled with unpatronizing sympathy and by firm exposition of the dynamics of hair growth.

 

Contents 13.1 13.2 13.3 13.3.1 13.3.2 13.3.2.1 13.3.2.2

Introduction  . . . . . . . . . . . . . . . . . . . . . . . . . History  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis  . . . . . . . . . . . . . . . . . . . . . . . . . Hair Follicle Cycling  . . . . . . . . . . . . . . . . . . Pathologic Dynamics of Hair Loss  . . . . . . Dystrophic Anagen Effluvium  . . . . . . . . . . Functional Types of Telogen Effluvium  . .

  260   260   260   260   261   261   261

13.4 13.4.1 13.4.1.1 13.4.1.2 13.4.2 13.4.2.1 13.4.2.2

Clinical Features  . . . . . . . . . . . . . . . . . . . . . Anagen Effluvium  . . . . . . . . . . . . . . . . . . . . Dystrophic Anagen Effluvium  . . . . . . . . . . Loose Anagen Hair  . . . . . . . . . . . . . . . . . . . Telogen Effluvium  . . . . . . . . . . . . . . . . . . . . Acute Telogen Effluvium  . . . . . . . . . . . . . . Chronic Telogen Effluvium  . . . . . . . . . . . .

  262   262   262   264   264   264   264

260

Ralph M. Trüeb 13.4.3 13.5 13.5.1 13.5.1.1 13.5.2 13.5.2.1 13.5.2.2 13.5.2.3

13.1

13

Quantitating Hair Loss  . . . . . . . . . . . . . . . . Differential Diagnosis  . . . . . . . . . . . . . . . . . Androgenetic Alopecia  . . . . . . . . . . . . . . . . Female Pattern Hair Loss  . . . . . . . . . . . . . . Psychogenic Pseudoeffluvium  . . . . . . . . . . Alopeciaphobia  . . . . . . . . . . . . . . . . . . . . . . Telogen Mania  . . . . . . . . . . . . . . . . . . . . . . . Delusion of Alopecia/Body Dysmorphic Disorder  . . . . . . . . . . . . . . . . . . . . . . . . . . . .

  265   268   268   268   268   268   268   268

Introduction

Few dermatologic complaints carry as much anxiety and emotional distress as hair loss. Equally, evaluation and management of hair loss are challenging. Most vexing may be the adult female presenting with diffuse hair loss [16]. Some men take the state of their hair seriously [14]; practically all women do [15]. The emotional overtones in this situation are often great; in some cases they seem disproportionate to the extent of hair loss. Misconceptions arise, as the patient obtains erroneous information from friends, hair dressers, and pharmacists [78]. Adding to the patient’s worry may be prior negative experiences with physicians, who trivialize complaints of hair loss. This attitude on the part of physicians may result from lack of knowledge, thereby making them uncomfortable dealing with such patients. Knowledge of the main types of hair loss is a prerequisite to providing appropriate patient care. Moreover, in addition to its obvious psychological importance, hair loss may be a manifestation of a more general medical problem.

13.2

History

Diffuse shedding of hair has been called “defluvium capillorum.” Sabouraud in 1932 [60] originally restricted the term to sudden diffuse loss of hair following shortly after a severe emotional shock, while others applied it to all forms of alopecia. During the 1950s “chronic diffuse alopecia” in women was differentiated from acute and reversible diffuse alopecia, attributable to a readily identifiable cause [72]. However, a majority of these patients were women with androgenetic alopecia of the female pattern who did not display any endocrinological abnormalities. The term was also used to describe women with diffuse hair loss of unexplored etiology, such as thyroid dysfunction or malnutrition. In 1960 Guy and Edmundson [28] described a form of chronic diffuse hair loss they called “diffuse cyclic hair loss in women” in which no specific trigger was evident. Finally, others assumed that a diffuse type of alopecia areata may ac-

  13.5.3 13.5.3.1 13.5.3.2 13.6

Alopecia Areata  . . . . . . . . . . . . . . . . . . . . . . Diffuse Alopecia Areata  . . . . . . . . . . . . . . . Chronic Diffuse Alopecia Areata/Diffuse Alopecia with Stem Cell Folliculitis  . . . . . Treatment  . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary for the Clinician  . . . . . . . . . . . . .

  268   269   269   269   270

References   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   270

count for some cases of alopecia diffusa [10]. In 1961 Kligman revealed the pathodynamics of one common pattern of response of hair follicles to a variety of insults and named it telogen effluvium [37]. On the basis of changes in different phases of the follicular cycle, Headington [32] later (in 1993) proposed classification of telogen effluvium into five functional types based on changes in different phases of the hair cycle, while Whiting [81] finally revived the concept of chronic telogen effluvium, additionally characterizing histopathologic features that delineate this entity from androgenetic alopecia.

13.3

Pathogenesis

Disease states that cause hair loss are categorized according to whether the hair loss is diffuse or localized, and to whether the follicle remains intact or is destroyed and replaced by scar. Except for the scarring alopecias, hair loss represents a disorder of hair follicle cycling [53]. Whatever the cause, the follicle tends to behave in a similar way. To grasp the meaning of this generalization requires understanding of the hair cycle and its derangements.

13.3.1 Hair Follicle Cycling The hair follicle is subject to constant turnover in the course of perpetual cycles through phases of proliferation (anagen), involution (catagen), and resting (telogen), with regeneration in the successive hair cycle [54]. It is a major characteristic of anagen that not only is the hair shaft growing but most epithelial hair follicle compartments are undergoing proliferation, with the hair matrix keratinocytes showing the highest proliferative activity. During catagen, hair follicles enter a process of involution that is characterized by a burst of programmed cell death (apoptosis) in the majority of follicular keratinocytes [6]. The resulting shortening of the regressing

Diffuse Hair Loss

epithelial strand is associated with an upwards movement of the follicle. In telogen, the hair shaft matures into a club hair, which is held tightly in the bulbous base of the follicular epithelium, before it is eventually shed. It is still unresolved whether shedding of the telogen hair (teloptosis) is an active, regulated process or represents a passive event that occurs at the onset of subsequent anagen, as the new hair grows in [57]. Cyclic hair growth activity occurs in a random mosaic pattern with each follicle possessing its own individual control mechanism over the evolution and triggering of the successive phases, though systemic factors such as the hormonal system, cytokines and growth factors, as well as external factors linked to the environment, such as toxins, and deficiencies of nutrients, vitamins, and energy. Finally, there are considerable variations in the length of these phases depending on the body site location, with the duration of anagen determining the type of hair produced, particularly its length [54]. On the scalp, hairs remain in anagen for a 2- to 6-year period of time, whereas telogen lasts for approximately 100 days, resulting in a ratio of anagen to telogen hairs of 9:1. On average, the amount of new scalp hair formation matches the amount that is shed, thereby maintaining a consistent covering. With a range of 75,000 to 150,000 hairs on the head, the reported average daily number of telogen hairs being shed varies, with published values of 35 [35], 40–100 [61], 100 [61, 71], 100–150 [21], and 100–180 hairs [80]. In general, the anagen phase is longer in women than in men [21].

13.3.2 Pathologic Dynamics of Hair Loss Many factors can lead to pathologically increased hair loss. The pathologic dynamics of hair loss can be related to disorders of hair cycling.

13.3.2.1

Dystrophic Anagen Effluvium

Dystrophic anagen effluvium is hair loss that results from the shedding of large numbers of hairs from the anagen phase of growth. It is a major characteristic of anagen that the epithelial hair follicle compartment undergoes proliferation, with the hair matrix keratinocytes showing the highest proliferative activity in building up the hair shaft. The common pathogenesis which unites the different etiologies of dystrophic anagen effluvium is a direct insult to the rapidly dividing bulb matrix cells. The abrupt cessation of mitotic activity leads to the weakening of the partially keratinized, proximal portion of the hair shaft, its narrowing and subsequent breakage

Chapter 13

a

261

b

Fig. 13.1a,b  a Dystrophic anagen hair (light microscopy), b telogen hairs (light micro­scopy)

within the hair canal and shedding. The morphological consequence is dystrophic anagen hair with a tapered proximal end and lack of root sheath (Fig. 13.1a).

13.3.2.2

Functional Types of Telogen Effluvium

Telogen effluvium is hair loss that results from increased shedding of hairs from the telogen phase of the hair cycle. An increase in the percentage of follicles in telogen to >20% leads to increased shedding of normal club hairs (Fig. 13.1b). On the basis of changes in different phases of the follicular cycle, Headington proposed classification of telogen effluvium into five functional types based on changes in different phases of the hair cycle [32]: 1. In immediate anagen release, follicles that would normally complete a longer cycle by remaining in anagen prematurely enter telogen. It is a very common form of telogen effluvium, typically occurring after periods of physiologic stress including episodes of high fever. In fever, the pyrogens, basically circulating cytokines, drive the hair follicle keratinocytes into apoptosis initiating catagen with following telogen. Because the shedding is dependent on transition from anagen through catagen and telogen with subsequent release of telogen hairs, hair loss occurs 3–4 months after the inciting event. 2. In delayed anagen release, hair follicles remain in prolonged anagen rather than cycling into telogen. When finally released from anagen, the clinical sign of increased shedding of telogen hair will be found. This type of telogen effluvium underlies post partum hair loss.

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3. In immediate telogen release, hair follicles normally programmed for release of the club hair after an interval of usually 100 days after the end of anagen are prematurely stimulated to cycle into anagen. There is premature teloptosis. This type of telogen effluvium underlies the shedding of hair upon initiation of therapy with topical minoxidil (shedding phase). 4. In delayed telogen release, hair follicles remain in prolonged telogen rather than being shed and recycling into anagen. When finally teloptosis sets in, again the clinical sign of increased shedding of club hairs is observed. This process underlies molting in mammals and probably also seasonal shedding of hairs in humans or mild telogen effluvia following travel from low-daylight to high-daylight conditions. 5. Finally, a short anagen phase (without synchronization) results in a slight but persistent telogen effluvium in association with decreased hair length: this may occur in hereditary hypotrichosis, ectodermal dysplasia (tricho-dental syndrome), and as an isolated disorder in otherwise healthy children [6]. Far more frequent is acquired progressive shortening of anagen due to androgenetic alopecia (see Sect.13.5).

13

13.4

Clinical Features

A simple office technique for evaluation of hair loss is to pull gently on the patient’s hair (hair pull test). Normally, one can come away with up to five hairs, but with pathologic hair loss this number is increased (positive hair pull). In diffuse hair loss the hair pull test is positive in both the vertex area and margins of the scalp. Diffuse hair loss is further classified by the types of hairs that are shed, in particular whether they are anagen hairs (anagen effluvium) or telogen hairs (telogen effluvium).

13.4.1 Anagen Effluvium Two types of anagen effluvium are recognized: dystrophic anagen effluvium and loose anagen hair.

13.4.1.1

Dystrophic Anagen Effluvium

Causes for dystrophic anagen effluvium are antineoplastic drugs (chemotherapy-induced alopecia), radiation (radiation-induced alopecia), environmental or occupational exposure to toxins (toxic alopecia), and alopecia areata (see Sect.13.5). All of these, as different as they are, have one thing in common which explains the exceptional phenomenon of anagen effluvium: they stop the reproduction of matrix cells; but, evidently mitotic

 

inhibition alone is not sufficient to force the follicle into catagen, and merely causes it to suspend operations. Presumably, the induction of catagen, normally or under pathologic conditions, is controlled by forces acting through the hair papilla rather than on the follicular epithelium directly. Chemotherapy-induced alopecia is understood to be the consequence of a direct toxic insult to the rapidly dividing bulb matrix cells of the hair follicle during anagen. With high doses of chemotherapy the hairs may be easily epilated in a week or two shortly followed by diffuse spontaneous hair loss. The usual change in the hair root is quite characteristic and consists of sharp thinning or constriction at which points the hairs simply separate. With lower doses there is only a segmental thinning or narrowing without fracture of the shaft at the point of weakness. When the drug is stopped, the follicle usually resumes its activity in a few weeks, having suffered no more than a temporary arrest in its growth. Another course of the drug produces these changes again. Even when these events are re-enacted many times by repeated courses, hair growth is usually only temporarily inhibited. After the hair has regrown, the telogen count is found to be the same even after repeated episodes of hair loss, showing that the hair cycles are not materially altered. Histologically there is a reduction in the volume of the hair bulb reflecting loss of epithelial cells, nonetheless the hairs continue in anagen. Clearly, chemotherapy-induced dystrophic anagen effluvium differs from telogen effluvium, also in terms of clinical presentation. Since up to 90% of scalp hair is in anagen at a given time, and anagen effluvium is not dependent on the transition from anagen to telogen with subsequent release of telogen hairs, hair loss is copious (80%–90%) and occurs within days to a few weeks of the causative event (Fig. 13.2). Nevertheless, experimental evidence also exists in the literature [9] that the hair follicle may respond to the same insult capable of stopping mitosis with both shedding patterns, i.e., dystrophic anagen effluvium and telogen effluvium. When an arrest of mitotic activity occurs, numerous and interacting factors influence the choice of the shedding pattern: one of these factors is the mitotic activity of the hair follicle at the moment of insult. When the hair is in its phase of highest mitotic rate, the arrest of mitosis causes differentiation to stop, producing a sharp constriction of the hair shaft and, therefore, its fracture. When the hair is in its late anagen phase, in which the mitotic rate is slowing down spontaneously, it simply accelerates its normal way to telogen. Finally, mitotically inactive phases of the hair cycle (catagen and telogen) are not affected. The intensity and duration of the antimitotic insult are also important. The incidence and severity of the hair loss are variable and related to the particular chemotherapeutic protocol. Chemotherapy given at a high dose for

Diffuse Hair Loss

Fig. 13.2  Dystrophic anagen effluvium following chemo­ therapy

a sufficiently long time may affect all hairs. The scalp is the most common location for hair loss; other terminal hairs are variably affected depending on the percentage of hairs in anagen. The beard, eyebrows, eyelashes, axillary, and pubic hairs may become involved with multiple exposures over a long period. Once the insult is removed, usually regrowth is prompt since normal anagen growth was only temporarily interrupted. Nevertheless, permanent alopecia following chemotherapy with busulfan after bone marrow transplantation has been reported [5, 76], and risk factors included chronic graft-versus-host reaction, prior exposure to X-ray, and older age [79]. Finally, there are circumstances in which telogen effluvium is the more likely to occur. The most common circumstance is androgenetic alopecia. In this condition, anagen duration is diminished and, consequently, the probability that the antimitotic insult strikes the hair close to the resting phase is increased. Synchronization of hair cycles also plays a role. The long duration of anagen is the main factor determining the individuality of the hair cycle in humans. Again, in androgenetic alopecia, the hair cycles tend to synchronize due to the diminished duration of anagen. Even a minor antimitotic insult, therefore, may produce marked hair loss. Radiation-induced alopecia may either be reversible or permanent. Radiation-induced temporary epilation may be observed following neuroradiologically guided embolization procedures [34]. Permanent alopecia occurs with >30 Gy of deep X-rays, or >50 Gy of soft Xrays [52]. Toxic alopecia from occupational exposure to hazardous chemicals has decreased over the years due to more stringent government regulations. More recently, interest has focused on mild aggressions from toxic metals of the environment. Many heavy metals are capable of disrupting the formation of the hair shaft through co-

Chapter 13

valent binding with the sulfhydryl groups in keratin: thallium, mercury, arsenic, copper, cadmium, and bismuth. A study conducted 1979 in Belgium reported diffuse alopecia related to ingestion of toxic metals in 36 of 78 patients with diffuse alopecia [56]. Toxic metals in abnormal amounts in blood and urine were observed only when >10% of hair bulbs were dystrophic. Copper was involved in 17 alopecias, arsenic in 12, mercury in 5, and cadmium in 2. Copper intoxication was found to be related to ingestion of tap water containing a high concentration of copper salts, presumably from low pH, the presence of chelating agents, or the connection of electrical ground wires to copper water pipes, which caused sufficient flow of electrical current to ionize the metal [56]. Adverse effects related to dental amalgam, including hair loss, have also been the subject of recent attention. In one study [8], mercury levels in blood and urine correlated with the number of amalgam surfaces, indicating the release of mercury from dental amalgam restorations. Since the mercury levels were far below those at which negative health effects would be expected and were similar in patients with complaints self-related to dental amalgam restorations and in healthy control individuals, mercury was not found to be a likely cause of the impaired health reported by the patients. In another study [41], assays of mercury in urine samples of patients with “amalgam illness” indicated that the exposure was far below the levels at which symptoms could be indicated by psychometric tests. Psychologic investigation indicated that the symptoms were psychosomatic. All patients had experienced important psychic traumata in close correlation with the first appearance of symptoms. Alopecia areata probably represents the most frequent cause of anagen dystrophic effluvium, either localized or diffuse, occurring in the otherwise healthy child (Fig. 13.3) or adult. Alopecia areata is regarded

Fig. 13.3  Dystrophic anagen effluvium in an otherwise healthy child due to alopecia areata

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as an organ-specific autoimmune disease, with the hair follicle being the target of autoimmunity. The cytokines generated by a peribulbar lymphocytic infiltrate cause apoptosis of the hair follicle keratinocytes.

13.4.1.2

13

Loose Anagen Hair

Loose anagen hair, characterized by easily pluckable anagen hairs, is a disorder predominantly described in children. The condition often recedes with age, but can be seen in adulthood, either as a continuation of the disorder that has lingered since childhood, or as late-onset loose anagen hair [74]. Loose anagen hair-like changes have also been associated with acquired immunodeficiency syndrome (AIDS trichopathy) [67]. Patients with late-onset loose anagen hair state that their hair has increased shedding and does not grow as long as it used to. Clinically the hair may show uneven ends. Additionally, there may be variations in hair texture, and the hair is often dry and lack luster. The diagnosis of loose anagen hair is based on the following criteria [74]: on pull test, painless extraction of more than ten anagen hairs; in the trichogram, >80% of plucked hairs are anagen hairs devoid of sheaths (Fig. 13.4). Histological studies of scalp biopsy samples have demonstrated abnormal clefting between the internal root sheath and the hair shaft [30], premature keratinization [58], and degeneration of the inner sheath [30]. Also, poor cohesion of the cells of the outer sheath has been described [4]. Ultrastructural studies show longitudinal grooves of the hair shaft. The presence of these alterations supports the hypothesis of some abnormality of the root sheath adversely affecting anchorage of the anagen hair in the follicle.

 

13.4.2 Telogen Effluvium Most patients with hair loss seen in clinical practice present with telogen effluvium. As telogen hairs have a depigmented bulb, examination of shed or pulled hairs with the naked eye will usually clarify this. In Kligman’s original description [37], telogen effluvium is an acute and diffuse hair loss brought about by a variety of triggers. Clinical experience, however, suggests that chronic telogen effluvium also exists. It is defined as diffuse telogen hair loss that persists >6 months.

13.4.2.1

Acute telogen effluvium presents as a diffuse, nonpatterned hair loss from the scalp that occurs around 3 months after a triggering event, and is usually selflimiting within 6 months by definition. A host of different triggers have been implicated and identify the cause, e.g., post-febrile, postpartum, psychogenic effluvium, etc. Severe febrile illness, childbirth, accidental trauma or surgical operations with large blood loss, a crash diet, or severe emotional distress are among the most common causes [68]. Hair loss is usually  6 months either represents a primary disorder and is

Diffuse Hair Loss

Chapter 13

Fig. 13.5  Chronic telogen effluvium: bitemporal thinning

then a diagnosis of exclusion, or is secondary to a variety of systemic disorders [70]: iron deficiency, other dietary deficiencies (protein-calorie malnutrition, zinc deficiency) [27], thyroid disease [17], other metabolic diseases (chronic renal or liver failure, advanced malignancy, pancreatic disease and upper gastrointestinal disorder with malabsorption), systemic lupus erythematosus [82], other connective tissue disorders [36], HIV infection [45], and drug-induced telogen hair loss [11, 42, 63, 73] (Table 13.1). Apart from iron deficiency as a cause of chronic diffuse hair loss, all others are less common, although the literature concerning iron deficiency remains controversial. Iron deficiency has been reported in the majority of women presenting with diffuse hair loss [64, 65], but this probably has been overestimated. More recent data suggest that in most women with chronic telogen effluvium, no direct relationship between low serum ferritin levels (≥20 µg/l) and hair loss exists [3, 69]. While chronic telogen effluvium may be triggered by an acute telogen effluvium, in primary chronic telogen effluvium no specific trigger is evident. It predominantly affects women, while men with short hair tend not to notice increased hair shedding. The presentation of this type of diffuse hair loss tends to be distinctive, and was first described in detail by Guy and Edmundson as “diffuse cyclic hair loss in women” [28], and revived by Whiting in 1996, who additionally characterized the histopathologic features [81]. The typical patient is a vigorous otherwise healthy woman between 30 and 60 with a full, thick head of hair. On examination there is some bitemporal recession and a positive hair pull test equally over the vertex and occiput. There is no widening of the central part, as is common in androgenetic alopecia. Nevertheless, patients are adamant that they previously had more hair and are distressed by the prospect of going bald. Many frequently bring large balls of hair for inspection (Fig. 13.6), but despite this do not show any

Fig. 13.6  Hair ball brought in by patient with chronic telogen effluvium

obvious balding. The condition tends to run a fluctuating course, at times reflecting seasonal periodicity in the growth and shedding of hair with a maximal proportion of telogen hairs at the end of summer and the beginning of autumn [19]. In the long run the disorder appears to be self-limiting. It is important to reassure patients that this condition represents exaggerated shedding rather than actual hair loss. It has been proposed that this disorder may be due to synchronization phenomena of the hair cycle [28], shortening of the anagen phase [32], or premature teloptosis [60]. As often happens in skin diseases in women, cosmetics are often thought to be the cause. Shampoos and hair colorants are blamed. While the absence of effects of shampoos on hair loss rates has been demonstrated [39], telogen effluvium after allergic contact dermatitis of the scalp has been reported [75].

13.4.3 Quantitating Hair Loss Reliably assessing the actual shedding of hair is a crucial diagnostic point in trichological practice. To fulfill office requirements, the test should be easy, non-invasive, and

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Table 13.1  Drugs responsible for diffuse hair loss (selection) Dystrophic anagen effluvium

Dystrophic anagen effluvium (continued)

Inhibition of mitosis (dystrophic anagen effluvium): cytostatic agents

Inhibition of mitosis (dystrophic anagen effluvium): cytostatic agents (continued)

Cytostatic agents which usually do cause hair loss:

Cytotoxic agents which unusually cause hair loss:

Adriamycin Docetaxel

Cisplatin

Paclitaxel

Capecitabine

Ifosfamide Irinotecan Vindesine

Telogen effluvium with known or assumed mechanism: Interference with keratinization process in the hair follicle: retinoids

Acitretin

Vinorelbine

Isotretinoin

Topotecan Amsacrine Vincristine Cytarabine Vinblastine Bleomycin Lomustine Busulfan

Interference with blood flow in follicular papilla: anticoagulants

Heparin

Interference with cholesterol synthesis: lipid-lowering agents

Fibrates (Clofibrate, Bezafibrate, Fenofibrate)

Complexation of zinc (thiol moiety): ACE inhibitors

Captopril

Interference with thyroid metabolism: thyrostatics and others

Propylthiouracil

Thiotepa

Methotrexate Procarbazine Carmustine 6-Marcaptopurine Mitroxantrone Streptozotocin Mitomycin C Fludarabine

Lovastatin

Enalapril

Levothyroxine

Lithium (antipsychotic)

Gemcitabine Melphalan

Warfarin

Amiodarone (anti-arrhythmic)

5-Fluorouracil

Cytotoxic agents which unusually cause hair loss:

Vitamin A (>50,000 I.E. daily)

Cyclophosphamide

Epirubicin

Cytotoxic agents which sometimes cause hair loss:

Raltritrexed

Daunorubicin

Etoposide

13

Carboplatin

Androgen effect: androgens, anabolics and progestins with androgenic effect

Mesterolone Testosterone Danazol Nandrolone Stanozolol Norethisterone Levonorgestrel Tibolone

Diffuse Hair Loss

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267

Table 13.1  (continued) Drugs responsible for diffuse hair loss (selection) Telogen effluvium with known or assumed mechanism (continued):

Telogen effluvium with unknown mechanism (in order of indications) (continued):

Aromatase inhibition: aromatase inhibitors

Antiepileptics

Cytokine effect: interferons

Letrozole Anastrozole

Paramethadione

Formestane

Clonazepam

Alpha interferon

Phenytoin

Gamma interferon

Ethotoin

Telogen effluvium with unknown mechanism (in order of indications): Blood-pressure-lowering agents (beta-blocking agents):

Acebutolol Nadolol Atenolol

Trimethadione Mephenytoin Antiepileptics

Valproic acid

Antibiotics/ tuberculostatics:

Thiamphenicol

Pindolol

Gentamicin Nitrofurantoin

Propranolol Metoprolol Betaxolol Timolol Levobunolol Analgesics/non steroidal anti-inflammatory agents:

Acetaminophen Piroxicam Ibuprofen Indomethacin Ketoprofen Penicillamine Naproxen Gold and gold compounds

Psychotropic agents/antidepressants:

Amitriptyline Haloperidol Desipramine Imipramine Doxepin Nortriptyline Fluoxetine Trimipramine

Isoniazid Ethambutol

Labetalol

Topical beta-blocking agents for therapy of glaucoma:

Carbamazepine

Varia

Chloroquine, hydroxychloroquine (antimalarials) Albendazole, mebendazole (anthelminthic agents) Cimetidine, famotidine, ranitidine (antacids) Allopurinol (uricostatic agent) Sulfasalazine (antiphlogistic/ sulfonamide) Bromocriptine (prolactin inhibitor/ anti Parkinson agent) Levodopa (anti-Parkinson agent) Halothane (inhalation anesthetic)

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not time-consuming. Many methods have been proposed, but all need standardization. The hair pull test has been found to be a poorly sensitive method, while telogen percentage in the trichogram does not correlate with severity of hair loss [26]. While the daily hair count is a cumbersome procedure, it has been proposed that the wash test is probably the best method to adopt [26]. In the wash test, the patient, 5  days after the last shampoo, washes the hair in the sink with its drain covered by gauze. The hairs entrapped in the gauze are then counted [48]. In one study assessing hair shedding in children, the wash test proved to be reliable, with a cutoff point of normality close to 11, and wash test values increasing with age [59]. More so, measurement of the effects of treatment needs to be quantified reliably. The method should be more sensitive than the wash test, and capable of analyzing relevant parameters of hair growth; namely, hair density, hair diameter, hair growth rate, and anagen/telogen ratio. For this purpose, a technique has been developed that combines epiluminescence microscopy with automatic digital image analysis (TrichoScan) [33].

13

13.5

Differential Diagnosis

The most important differential diagnoses of diffuse telogen hair loss include androgenetic alopecia and psychogenic pseudoeffluvium. There is considerable overlap between the two, further complicating differential diagnosis, especially in women [77]. Far less common is diffuse alopecia areata.

13.5.1 Androgenetic Alopecia Androgenetic alopecia is the most common cause of hair loss in men (Chap. 9) and in women (Chap. 10). It is characterized by hair loss in a distinctive pattern that differs between men (male pattern hair loss) [29, 46] and women (female pattern hair loss) [43]. In the early stages of androgenetic alopecia the pattern may not be apparent, and patients may complain of diffuse hair loss. This presentation is far more common in women, and is sometimes observed in children of both sexes with a prepubertal onset of androgenetic alopecia [7]. This can pose diagnostic difficulties.

13.5.1.1

Female Pattern Hair Loss

Recent literature suggests that patterned hair loss may have different mechanisms in men and in women [47].

 

Because the androgen dependence of hair loss in all women with this type of alopecia has not been sufficiently demonstrated, and it has been observed in the absence of circulating androgens [51], the term female pattern hair loss has been proposed to replace androgenetic alopecia when applied in women [49, 50]. Nevertheless, female pattern hair loss shares with androgenetic alopecia the histolopathologic feature of hair follicle miniaturization. A terminal-to-vellus ratio of 7:1 suggests chronic telogen effluvium [80].

13.5.2 Psychogenic Pseudoeffluvium Patients seeking advice for hair loss are not necessarily balding. When they have normally dense scalp hair, and absence of any convincing evidence of hair loss, they are regarded as suffering of “imaginary hair loss” or psychogenic pseudoeffluvium. In these cases thought should be given to underlying psychological disorders.

13.5.2.1

Alopeciaphobia

Mild instances of alopeciaphobia [37] are common in connection with depressive disorder.

13.5.2.2

Telogen Mania

Some extremely hair-conscious patients are capable of fierce fits of hair brushing, telogen mania, which is perhaps a modified form of obsessive-compulsive disorder or trichotillomania [37].

13.5.2.3

Delusion of Alopecia/Body Dysmorphic Disorder

Finally, the physician should be aware of the potential seriousness of delusion of alopecia and of body dysmorphic disorder [18], both nearly psychotic states.

13.5.3 Alopecia Areata Alopecia areata (see Chap. 15) is an immune-mediated form of hair loss, which commonly presents as localized patches of bald scalp. An as yet unidentified trigger stimulates an autoimmune lymphocytic attack on the hair bulb. The inflammation is specific for anagen hairs and causes anagen arrest.

Diffuse Hair Loss

13.5.3.1

Diffuse Alopecia Areata

With a proportion of 2%, diffuse alopecia areata is the least common clinical type of alopecia areata, and is largely confined to the >40 age group [44]. It lacks the characteristic patches of alopecia and instead demonstrates widespread thinning that is severe and rapidly progressive, often evolving to total hair loss. The patient with diffuse alopecia areata may also complain of rapid graying of hair (Fig. 13.7).

13.5.3.2

Chronic Diffuse Alopecia Areata/Diffuse Alopecia with Stem Cell Folliculitis

Chronic diffuse alopecia areata is particularly rare. Patients present with profound hair loss, but often are not actively shedding. The alopecia may have a slightly reticular pattern. Where no patch of alopecia coexists as a clue to the diagnosis, a biopsy is usually required to establish the identification. Optimal specimens include two 4-mm punch biopsy specimens from the vertex submitted for horizontal and vertical embedding [22]. The histologic features depend on the stage of the disease, and biopsy specimens of clinically active alopecia areata show peribulbar lymphocytic infiltrates around anagen follicles [31]. Especially in biopsy specimens from long-standing areas of alopecia areata with an increased number of telogen follicles and follicular miniaturization, the histology is sometimes equivocal, since a light perifollicular lymphocytic infiltrate can be a non-specific histologic finding. In this context, it is not clear whether Kossard’s diffuse alopecia with stem cell folliculitis [38] represents chronic diffuse alopecia areata or a distinct entity. Further studies to clarify this issue are warranted.

Fig. 13.7  Diffuse alopecia areata with graying of hair

Chapter 13

A response with hair regrowth to oral prednisolone in doses >0.5 mg/kg for 3–4 weeks with subsequent tapering is sometimes required to establish the diagnosis of diffuse alopecia areata [68].

13.6

Treatment

Management and prognosis of diffuse hair loss depend on the cause and underlying pathomechanism in its relation to the hair growth cycle. Most acute telogen effluvia, particularly those due to acute-onset physiologic events (e.g., postfebrile, postpartum), as well as mild seasonal telogen effluvium, and the shedding phase observed upon initiation of topical minoxidil treatment are self-limiting and will undergo normal reversal. The cause of chronic telogen effluvium may be multifactorial and difficult to establish. Systemic diseases known to cause telogen effluvium, such as iron deficiency, thyroid dysfunction, systemic lupus erythematosus, and syphilis, need to be systematically excluded or treated. Drugs known to cause hair loss, such as anticoagulants (heparin, warfarin), oral retinoids (acitretin, isotretinoin), interferon, agents with antithyroid action (carbimazole, propylthiouracil, amiodarone), hypolipidemic agents (fibrates), colchicine, antimetabolites (methotrexate, azathioprine, cyclophosphamide), and hormones with pro-androgen action (norethisterone, levonorgestrel, tibolone) should be discontinued unless they are essential for the patient. Finally, in young women, the diet should be addressed. If anorexia nervosa/bulimia is suspected, the aid of a psychiatrist should be sought; in other cases the informed patient will be happy to abandon any dietary culprit. Differential diagnosis may be complicated by considerable overlap, especially with androgenetic alopecia; for instance, postpartum effluvium after which the hair does not necessarily return to the same antepartum texture and length. In these cases the addition of topical minoxidil to the treatment regimen is usually helpful. Synchronization phenomena of hair cycling, also on a seasonal basis, seem to be more pronounced in patients with androgenetic alopecia, since with a shorter anagen phase a greater proportion of hair follicles will synchronize. Recommendations for treatment of primary chronic telogen effluvium are scanty, and include topical or systemic corticosteroids [28], topical minoxidil [60], and dietary supplements on the basis of millet extract [1], pantothenic acid, biotin [23], their combination [20], and combinations of L-cystine, medicinal yeast and pantothenic acid (“CYP-complex”). The rationale for the use of L-cystine is based on the biochemistry of cys-

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tine metabolism, clinical observations in disorders of cystine metabolism and cystine deficiency, and results of animal and human studies. In the 1960s, the role of L-cystine in the production of wool was investigated, and it was found that enrichment of even what appeared to be a normal diet with sulfur-containing amino acids increased wool production in sheep [24, 25, 62]. When considering which dietary supplements could be used to improve hair growth in humans, L-cystine was therefore a candidate. In the early 1990s studies on the effect of dietary supplements containing L-cystine in combination with B-complex vitamins and medicinal yeast, a rich natural source of B-complex vitamins, were published and showed improvements in the trichogram, in hair swelling as a criterion for hair quality, and in the tensile strength of the hair fiber [12, 55]. One double-blind, placebo-controlled study performed with the TrichoScan technique in 30 otherwise healthy women suffering from telogen effluvium demonstrated that a dietary supplement with “CYP-complex” increased the anagen hair rate within 6 months of treatment, while placebo did not [40]. The supplement did not have any effect on terminal hair counts, hair density, and cumulative hair shaft diameter, and thus would not seem to be indicated for treatment of alopecia due to cycle shortening, such as androgenetic alopecia. Since synchronization phenomena tend to complicate the course of alopecias due to anagen shortening, adding a CYP-complex-based dietary supplement to the treatment with minoxidil may nevertheless be beneficial. It has been shown in whole hair follicle cultures that minoxidil not only increases the incorporation of thymidine as a marker of cell division, but also leads to an increased uptake of cysteine by the hair follicle [13]. Most importantly, women with chronic telogen effluvium need to be reassured that it represents exaggerated shedding rather than actual hair loss and that the shed hair is mostly being replaced; therefore, the risk of total baldness is remote [47]. Finally, the issues of psychogenic effluvium and of overvalued ideas in relation to the condition of the hair are not always easy to resolve; however, it is important to control stress as a complication of hair loss or fear of hair loss. For this purpose strong psychological support is essential to help limit patient anxiety, and patients need to be educated about the basics of the hair cycle. Information about the hair cycle can be useful to explain how an effluvium not related to cycle shortening (as in androgenetic alopecia) generally precedes new regrowth, and why considerable patience is required for effective cosmetic recovery.

 

Summary for the Clinician Diffuse hair loss is a common complaint, and it is paramount that the physician addresses this symptom seriously. The diagnosis can usually be established with a history, particularly focusing on the chronology of events, examination of the scalp, pattern of hair loss, results of a pull test, examination of the bulbs of the shed hairs, and a few pertinent screening blood tests. In chronic cases a scalp biopsy may be required. Once the diagnosis has been established, treatment appropriate for that diagnosis is likely to control the hair loss except in chronic telogen effluvium. Patients with chronic telogen effluvium, as well as patients with overvalued ideas with respect to the condition of their hair can, however, be handled satisfactorily by unpatronizing sympathy from a knowledgeable and caring physician and firm exposition of the dynamics of hair growth.

R eferences 1. 2.

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Ahrens J (1994) Systemische Behandlung des diffusen Haarausfalls. Therapiewoche Schweiz 10:551–554 Arck PC, Handjiski B, Hagen E et al (2001) Indications for a ‘brain-hair follicle axis (BHA)’: inhibition of keratinocyte proliferation and up-regulation of keratinocyte apoptosis in telogen hair follicles by stress and substance P. FASEB J 15:2536–2538 Aydingöz IE, Ferhanoglu B, Güney O (1999) Does tissue iron status have a role in female alopecia? J Eur Acad Dermatol Venereol 13:65–67 Baden HP, Kvedar JC, Magro CM (1992) Loose anagen hair as a cause of hereditary hair loss in children. Arch Dermatol 128:1349–1353 Baker B, Wilson C, Davis A et al (1991) Busulphan/cyclophosphamide conditioning for bone marrow transplantation may lead o failure of hair regrowth. Bone Marrow Transpl 7:43–47 Barraud-Klenovsek MM, Trüeb RM (2000) Congenital hypotrichosis due to short anagen. Br J Dermatol 143:612–617 Borelli S, Trüeb RM (1999) Androgenetic alopecia with prepubertal onset? Dermatology 199:96 Bratel J, Haraldson T, Meding B et al (1997) Potential side effects of dental amalgam restorations. An oral and medical investigation. Eur J Oral Sci 105:234–243

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Braun-Falco O (1966) Dynamik des normalen und pathologischen Haarwachstums. Arch Klein Exp Dermatol 227:418–452 Braun-Falco O, Zaun H (1963) Über die Beteiligung des gesamten Capillitiums bei Alopecia areata. Hautarzt 13:342 Brodin M (1987) Drug-related alopecia. Dermatol Clin 5:571–579 Budde J, Tronnier H, Rahlfs VW et al (1993) Systemische Therapie von diffusem Effluvium und Haarstrukturschäden. Hautarzt 44:380–384 Buhl AE, Waldon DJ, Kawabe TT et al (1989) Minoxidil stimulates mouse vibrissae follicles in organ culture. J Invest Dermatol 92:315–20 Cash TF (1992) The psychological effects of androgenetic alopecia in men. J Am Acad Dermatol 26:926–931 Cash TF, Price VH, Savin RC (1993) Psychological effects of androgenetic alopecia on women: comparisons with balding men and with female control subjects. J Am Acad Dermatol 25:569–575 Chartier MB, Hoss DMM, Grant-Kels JM (2002) Approach to the adult female patient with diffuse nonscarring alopecia. J Am Acad Dermatol 47:809–818 Comaisch S (1985) The thyroid and hair growth. Semin Dermatol 4:4–8 Cotterill JA (1996) Body dysmorphic disorder. Dermatol Clin 14:457–463 Courtois M, Loussouarn G, Horseau S et al (1996) Periodicity in the growth and shedding of hair. Br J Dermatol 134:47–54 Dupré A, Lassère J, Christol B et al (1977) Traitement des alopécies diffuses chroniques par le panthénol et la D-biotine injectables. Rev Med Toulouse 13 :675–677 Ebling FJ, Rook A. Hair. In: Rook A, Wilkinson DS, Ebling EJB (eds.) (1968) Textbook of Dermatology, Vol 2. Blackwell Scientific Publications, Oxford, pp.1355–1425 Elston DM, McCollough ML, Angeloni VL (1995) Vertical and transverse sections of alopecia biopsy specimens. Combining the two to maximize diagnostic yield. J Am Acad Dermatol 32:454–457 Floersheim GL (1992) Prüfung der Wirkung von Biotin auf Haarausfall und Haarqualität. Z Hautkrankheiten 67 Frenkel MJ, Gillepsie JM, Reis PJ (1974) Factors influencing the biosynthesis of the tyrosine-rich proteins of wool. Aust J Biol Sci 27:31–38 Gillespie JM, Reis PJ (1966) Dietary regulated biosynthesis of high-sulfur wool proteins. Biochem. J 98:669–677 Guarrera M, Semino MT, Rebora A (1997) Quantitating hair loss in women: a critical approach. Dermatology 1997:12–16 Gummer CL (1985) Diet and hair loss. Semin Dermatol 4:35–39 Guy WB, Edmundson WF (1960) Diffuse cyclic hair loss in women. Arch Dermatol 81:205–227

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Hamilton JB (1951) Patterned loss of hair in man: types and incidence. Ann NY Acad Sci 53:708–728 Hamm H, Traupe H (1989) Loose anagen hair of childhood: the phenomenon of easily pluckable hair. J Am Acad Dermatol 20:242–248 Headington JT (1991) The histopathology of alopecia areata (abstract) J Invest Dermatol 96 (Suppl):69S Headington JT (1993) Telogen effluvium. New concepts and review. Arch Dermatol 129:356–363 Hoffmann R (2001) TrichoScan: combining epiluminiscence microscopy with digital image analysis for the measurement of hair growth in vivo. Eur J Dermatol 11:362–368 Huda W, Peters KR (1994) Radiation-induced temporary epilation after a neuroradiologically guided embolization procedure. Radiology 193:642–644 Ihm CW, Lee JY (1991) Evaluation in daily hair counts. Dermatologica 182:67 Kasteler JS, Callen JP (1994) Scalp involvement in dermatomyositis. Often overlooked or misdiagnosed. JAMA 272:1939–1941 Kligman AM (1961) Pathologic dynamics of human hair loss, I: telogen effluvium. Arch Dermatol 83:175–198 Kossard S (1999) Diffuse alopecia with stem cell folliculitis. Chronic diffuse alopecia areata or a distinct entity? Am J Dermatopathol 21:46–50 Kullavanijaya P, Gritiyarangsan P, Bisalbutra P et al (1992) Absence of effects of dimethicone- and nondimethicone-containing shampoos on daily hair loss rates. J Soc Cosmet Chem 43:195–206 Lengg N, Heidecker B, Seifert B et al (2007) Dietary supplement increases anagen hair rate in women with telogen effluvium: results of a double-blind placebocontrolled trial. Therapy 4:59–65 Lindberg NE, Lindberg E, Larsson G (1994) Psychologic factors in the eiology of amalgam illness. Acta Odontol Scand 52:219–228 Llau ME, Virabin R. Montastruc JL (1995) Les aopecies medicamenteuses: revue de la literature. Therapie 50:145–150 Ludwig E (1977) Classification of the types of androgenetic alopecia (common baldness) occurring in the female sex. Br J Dermatol 97:247–254 McDonagh AJG, MacDonald-Hull SP, Messenger AG et al (2003) Clinical subtypes and disease associations with alopecia areata (abstract P-21). In: European Hair Research Society 10th Meeting 2003. Proceedings: p. 39 Mirmirani P, Hessol N, Maurer T et al (2001) Prevalence of hair disorders in the women’s interagency HIV study (abstract 265). J Invest Dermatol 117:434 Norwood OT (1975) Male pattern baldness: classification and incidence. South Med J 68:1359–1365 Norwood O, Lehr B (2000) Female androgenetic alopecia: a separate entity. Dermatol Surg 26:679–682

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13

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Olsen EA. Clinical tools for assessing hair loss. In: Olsen EA (ed.) (1993) Disorders of Hair Growth: Diagnosis and Treatment. New York, McGraw-Hill, pp 59–69 Olsen EA (2001) Female pattern hair loss. J Am Acad Dermatol 45 (Suppl):S69–S119 Olsen EA, Hordinsky M, Roberts JL et al (2002) Female pattern hair loss. J Am Acad Dermatol 47:795 Orme S, Cullen DR, Messenger AG (1999) Diffuse female hair loss: are androgens necessary? Br J Dermatol 141:521–523 Panizzon RG, Goldtschmitdt H. Radiation reactions and sequelae. In: Goldschmidt H, Panizzon (eds.) (1991) Modern Radiation Therapy. Springer, Berlin Heidelberg New York Paus R (1996) Control of the hair cycle and hair diseases as cycling disorders. Curr Opin Dermatol 3:248–258 Paus R, Cotsarelis G (1999) The biology of hair follicles. N Engl J Med 341:491–497 Petri H, Perchalla P, Tronnier H (1990) Die Wirksamkeit einer medikamentösen Therapie bei Haarstrukturschäden und diffusen Effluvien – vergleichende Doppelblindstudie. Schweiz Rundsch Med Prax 79:1457–1462 Pierard GE (1979) Toxic effects of metals from the environment on hair growth and structure. J Cutan Pathol 6:237–242 Pierard-Franchimont C, Pierard GE (2001) Teloptosis, a turning point in hair shedding biorhythms. Dermatology 203:115–117 Price VH, Gummer CL (1989) Loose anagen syndrome. J Am Acad Dermatol 20:249–256 Rampini P, Guarrera M, Rampini E, et al (1999) Assessing hair shedding in children. Dermatology 199:256–257 Rebora A (1997) Telogen effluvium. Dermatology 195:209–212 Reeves JRT, Maibach HI, Drug and chemical induced hair loss. In: Marzulli FN, Maibach HI (eds.) (1977) Advances in Modern Toxicology, Vol 4. Hemisphere Publishing, Washington, pp. 487–500 Reis PJ, Tunks DA, Sharry LF (1973) Plasma amino acid patterns in sheep receiving abomasal infusions of methionine and cystine. Aust J Biol Sci 26:635–644 Roudier-Pujol C, Jan V (2000) Alopecies medicamenteuses. Ann Dermatol Venereol Suppl 127:26–28 Rushton DH (1993) Management of hair loss in women. Dermatol Clin 11:47–53 Rushton DH, Ramsay ID, James KC (1990) Biochemical and trichological characterization of diffuse alopeca in women. Br J Dermatol 123:187–197 Sabouraud R (1932) Diagnostic et Traitement des Affections du Cuir Chevelu. Paris, Masson

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Sadick NS (1993) Clinical and laboratory evaluation of AIDS trichopathy. Int J Dermatol 32:33–38 Sinclair R (1999) Diffuse hair loss. Int J Dermatol 38 (Suppl. 1):8–18 Sinclair R (2002) There is no clear association between low serum ferritin and chronic diffuse telogen hair loss. Br J Dermatol 147:982–984 Spencer LV, Callen JP (1987) Hair loss in systemic disease. Dermatol Clin 5:565–570 Stroud JP (1987) Diagnosis and management of the hair loss patient. Cutis 40:272–276 Sulzberger MB, Witten VH, Kopf AW (1960) Diffuse alopecia in women. Arch Dermatol 81:556 Tosti A, Misciali C, Piraccini BM et al (1994) Druginduced hair loss and hair growth. Incidence, management and avoidance. Drug Saf 10:310–317 Tosti A, Peluso AM, Misciali C et al (1997) Loose anagen hair. Arch Dermatol 133:1089–1093 Tosti A, Piraccini BM, van Neste DJ (2001) Telogen effluvium after allergic contact dermatitis of the scalp. Arch Dermatol 137:187–190 Tran D, Sinclair RD, Schwarer AP et al (2000) Permanent alopecia following chemotherapy and bone marrow transplantation. Austral J Dermatol 41:106–108 Trüeb RM (2000) Idiopathic chronic telogen effluvium in women. Hautarzt 51:899–905 Trüeb RM, Swiss Trichology Study Group (2000) Interaction between the medical profession, hairdressers and the media in the management of hair loss. Hautarzt 51:729–732 Vowels M, Chan LL, Giri N et al (1993) Factors affecting hair regrowth after bone marrow transplanttion. Bone Marrow Transpl 347–350 Whiting D (1993) Diagnostic and predictive value of horizontal sections of scalp biopsy specimens in male pattern androgenetic alopecia. J Am Acad Dermatol 28:755–763 Whiting DA (1996) Chronic telogen effluvium: increased scalp hair shedding in middle-aged women. J Am Acad Dermatol 35:899–906 Wysenbeek AI, Leibovici L, Amit M, et al (1991) Alopecia in systemic lupus erythematosus. Relation to disease manifestations. J Rheumatol 18:1185–1186 York J, Nicholson T, Minors P, et al (1998) Stressful life events and loss of hair among adult women, a case-control study. Psychol Rep 82:1044–1046 Zviak C, Dawber R. Hair structure, function and physicochemical properties. In: Zvaik C (ed.) (1986) The Science of Hair Care. Marcel Dekker, New York, pp. 1–48

Chapter 14

14

Hair Loss in Children Natalie Garcia Bartels, Ulrike Blume-Peytavi

 

 

6

Synonyms hair loss in neonates and children, hair shaft defects, genotrichoses, congenital alopecia, hypotrichia, atrichia, non-scarring alopecia, scarring alopecia



Key Features

• Hair loss in children comprises a broad spectrum of disorders. • Hair shaft defects with increased fragility simulate hair loss and should be considered in children with abnormal hair growth. Hair loss may present as localized, patchy or as diffuse alopecia. Close inspection of the scalp helps to further differentiate between non-scarring alopecia and scarring alopecia.

• •

• In children, a thorough clinical examination is man-

datory in all forms of hair loss to detect associated anomalies or diseases. Interdisciplinary work up is often required in children with hair loss. Careful guidance of the parents is needed to support coping with the diseases.

• •

 

Contents 14.1 14.1.1 14.1.1.1 14.1.1.2 14.1.1.3 14.1.1.4 14.1.1.5 14.1.1.6 14.1.1.7 14.1.1.8 14.1.2 14.1.2.1 14.1.2.2 14.1.2.3 14.1.2.4 14.1.2.5 14.1.2.6 14.1.2.7

Hair Shaft Defects Simulating Hair Loss  . Trichorrhexis Nodosa Congenita  . . . . . . . Introduction   . . . . . . . . . . . . . . . . . . . . . . . . History   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology  . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis   . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features  . . . . . . . . . . . . . . . . . . . . . Pathology   . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis   . . . . . . . . . . . . . . . . Treatment  . . . . . . . . . . . . . . . . . . . . . . . . . . . Monilethrix  . . . . . . . . . . . . . . . . . . . . . . . . . Introduction   . . . . . . . . . . . . . . . . . . . . . . . . History   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology  . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis   . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features   . . . . . . . . . . . . . . . . . . . . . Pathology   . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis  . . . . . . . . . . . . . . . . .

  276   276   277   277   278   278   278   278   278   278   278   278   279   279   279   279   280   280

14.1.2.8 14.1.3 14.1.3.1 14.1.3.2 14.1.3.3 14.1.3.4 14.1.3.5 14.1.3.6 14.1.3.7 14.1.3.8 14.1.4 14.1.4.1 14.1.4.2 14.1.4.3 14.1.4.4 14.1.4.5 14.1.4.6 14.1.4.7

Treatment   . . . . . . . . . . . . . . . . . . . . . . . . . . Pseudomonilethrix  . . . . . . . . . . . . . . . . . . . Introduction  . . . . . . . . . . . . . . . . . . . . . . . . . History   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology   . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis  . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features   . . . . . . . . . . . . . . . . . . . . . Pathology  . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis  . . . . . . . . . . . . . . . . . Treatment   . . . . . . . . . . . . . . . . . . . . . . . . . . Pili Torti  . . . . . . . . . . . . . . . . . . . . . . . . . . . . Introduction  . . . . . . . . . . . . . . . . . . . . . . . . . History  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology  . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis  . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features   . . . . . . . . . . . . . . . . . . . . . Pathology   . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis  . . . . . . . . . . . . . . . . .

  280   280   280   280   281   281   281   281   281   281   281   281   281   281   282   282   282   282

274

14

Natalie Garcia Bartels, Ulrike Blume-Peytavi 14.1.4.8 14.1.5 14.1.5.1 14.1.5.2 14.1.5.3 14.1.5.4 14.1.5.5 14.1.5.6 14.1.5.7 14.1.5.8 14.1.6 14.1.6.1 14.1.6.2 14.1.6.3 14.1.6.4 14.1.6.5 14.1.6.6 14.1.6.7 14.1.6.8 14.1.7 14.1.7.1 14.1.7.2 14.1.7.3 14.1.7.4 14.1.7.5 14.1.7.6 14.1.7.7 14.1.7.8 14.1.8 14.1.8.1 14.1.8.2 14.1.8.3 14.1.8.4 14.1.8.5 14.1.8.6 14.1.8.7

Treatment  . . . . . . . . . . . . . . . . . . . . . . . . . . . Menkes Disease  . . . . . . . . . . . . . . . . . . . . . . Introduction  . . . . . . . . . . . . . . . . . . . . . . . . . History   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology   . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis  . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features   . . . . . . . . . . . . . . . . . . . . . Pathology  . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis  . . . . . . . . . . . . . . . . . Treatment   . . . . . . . . . . . . . . . . . . . . . . . . . . Netherton Syndrome  . . . . . . . . . . . . . . . . . Introduction  . . . . . . . . . . . . . . . . . . . . . . . . . History  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology   . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis  . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features   . . . . . . . . . . . . . . . . . . . . . Pathology  . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis   . . . . . . . . . . . . . . . . Treatment  . . . . . . . . . . . . . . . . . . . . . . . . . . . Trichothiodystrophy  . . . . . . . . . . . . . . . . . . Introduction  . . . . . . . . . . . . . . . . . . . . . . . . . History   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology   . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis  . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features   . . . . . . . . . . . . . . . . . . . . . Pathology  . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis  . . . . . . . . . . . . . . . . . Treatment   . . . . . . . . . . . . . . . . . . . . . . . . . . Ectodermal Dysplasia  . . . . . . . . . . . . . . . . . Introduction  . . . . . . . . . . . . . . . . . . . . . . . . . History   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology   . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis  . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features   . . . . . . . . . . . . . . . . . . . . . Pathology  . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis  . . . . . . . . . . . . . . . . .

  283   283   283   283   283   283   284   284   284   284   284   284   284   284   285   285   285   286   286   286   286   286   286   286   287   287   287   287   287   287   288   288   288   288   289   289

Hair loss in neonates and children is frequently regarded as an alarming symptom by parents and pediatricians. A careful work up and a critical consideration, as to whether physiological or pathological causes are responsible, are highly important for clarification of the etiology. Age of onset is a helpful tool to sort the diagnostic approach considering main differential diagnoses of hair loss in childhood (Table 14.1). After a close clinical inspection hair loss can be further classified according to its clinical pattern (Table 14.2). However, basic knowledge of hair follicle development, hair biology and physiology is important for critical analysis and classification of the different conditions. Hair follicles begin their development around the 14th gestational week and show rapid growth, with hair

  14.1.8.8 14.1.9 14.1.9.1 14.1.9.2 14.1.9.3 14.1.9.4 14.1.9.5 14.1.9.6 14.1.9.7 14.1.9.8 14.2 14.2.1 14.2.1.1 14.2.1.2 14.2.1.3 14.2.1.4 14.2.1.5 14.2.2 14.2.2.1 14.3 14.3.1 14.3.1.1 14.3.1.2 14.3.1.3 14.3.1.4 14.3.1.5 14.3.1.6 14.3.2 14.3.2.1 14.3.2.2

Treatment   . . . . . . . . . . . . . . . . . . . . . . . . . . Acquired Hair Shaft Defects with Fractures: Weathering  . . . . . . . . . . . . Introduction  . . . . . . . . . . . . . . . . . . . . . . . . . History  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology  . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis  . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features   . . . . . . . . . . . . . . . . . . . . . Pathology  . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis  . . . . . . . . . . . . . . . . . Treatment  . . . . . . . . . . . . . . . . . . . . . . . . . . . Localized Hair Loss   . . . . . . . . . . . . . . . . . . Non-Scarring Alopecia  . . . . . . . . . . . . . . . . Alopecia Areata  . . . . . . . . . . . . . . . . . . . . . . Tinea Capitis  . . . . . . . . . . . . . . . . . . . . . . . . Trichotillomania  . . . . . . . . . . . . . . . . . . . . . Traction Alopecia  . . . . . . . . . . . . . . . . . . . . Triangular Alopecia  . . . . . . . . . . . . . . . . . . Scarring Alopecia  . . . . . . . . . . . . . . . . . . . . Congenital Aplasia Cutis  . . . . . . . . . . . . . . Diffuse Hair Loss   . . . . . . . . . . . . . . . . . . . . Non-Scarring Alopecia  . . . . . . . . . . . . . . . . Telogen Effluvium  . . . . . . . . . . . . . . . . . . . . Alopecia Areata Diffusa, Totalis or Universalis  . . . . . . . . . . . . . . . . . Loose Anagen Hair  . . . . . . . . . . . . . . . . . . . Hypotrichosis Simplex  . . . . . . . . . . . . . . . . Congenital Hypotrichia Marie Unna  . . . . Atrichia with Papular Lesions  . . . . . . . . . . Scarring Alopecia  . . . . . . . . . . . . . . . . . . . . Keratosis Follicularis Spinulosa Decalvans  . . . . . . . . . . . . . . . . . . . . . . . . . . . Pseudopelade of Brocq  . . . . . . . . . . . . . . . . Summary for the Clinician  . . . . . . . . . . . . .

  289   290   290   290   290   290   290   290   291   291   291   291   291   292   293   294   295   296   296   297   297   298   299   299   301   301   302   303   303   304   305

References   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   306

shafts visible by the 18th week [43]. Lanugo hair (fine, unpigmented, unmedullated, up to several centimeters in length) covering the scalp with development in a cephalocaudal direction covers possibly the whole fetus by the end of the second trimester. Physiological shedding of lanugo hair occurs during the 7th to 8th month of intrauterine life and is rapidly replaced by vellus hair on the body and terminal or vellus hair on the scalp [7, 20]. This transition wave may be delayed in the occipital area at 2–4 months postpartum explaining the circumscribed alopecia on the occiput of newborns at this age. Total follicle density of the scalp has been reported to be 1135 hairs/cm² at birth; as the body surface increases there is a decrease in the actual density of follicles with increasing age. Scalp terminal hair shows synchronous

Hair Loss in Children

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275

Table 14.1  Main differential diagnoses of hair loss in childhood, subdivided according to age at onset [56] Age group (years) 1–3

4–11

12–18

Genetic hair shaft defects

Autoimmune-inflammatory hair loss

Autoimmune-inflammatory hair loss

Congenital hypo-, atrichia and aplasia

Acquired hair shaft defects

Acquired localized non-scarring hair loss

Scalp infection (rare)

Scalp infection

Hormonal dysregulation androgen alopecia

Autoimmune-inflammatory hair loss (rare)

Acquired diffuse non-scarring hair loss

Androgenetic alopecia

Congenital hypotrichia (rare)

Acquired diffuse non-scarring hair loss Scarring alopecia (rare)

Table 14.2  Classification of hair loss according to its clinical patterna [56] Hair shaft defects simulating hair loss Genetic

Trichorrhexis nodosa

Acquired

Weathering

Monilethrix

Bubble hair

Pseudomonilethrix

Trichorrhexis nodosa

Pili torti Netherton Syndrome Menkes Syndrome Trichothiodystrophy Ectodermal dysplasia Localized hair loss with non-scarring alopecia

Alopecia areata Tinea capitis, folliculitis/pyodermia

Diffuse hair loss with non-scarring alopecia

Telogen effluvium Alopecia areata diffusa, totalis or universalis

Trichotillomania

Loose anagen hair

Traction alopecia

Congenital hypo- and atrichia

Triangular alopecia Loose anagen hair Localized hair loss with scarring alopecia

Congenital aplasia cutis Deep fungal, bacterial or viral infection Physical, chemical or mechanically induced scarring alopecia

a

Most frequent disorders are presented.

Diffuse hair loss with scarring alopecia

Keratosis follicularis spinulosa decalvans Pseudopelade Brocq

276

Natalie Garcia Bartels, Ulrike Blume-Peytavi

hair growth activity until the end of the first year of life, with physiological increased shedding at the end of this period due to individual cycling and asynchronous hair growth activity of each hair follicle. Pathological hair loss rarely occurs during the first year of life but may be a leading symptom of congenital diseases. For the classification of pathological hair loss in children, three major groups should be differentiated: hair shaft defects simulating hair loss, localized hair loss, and diffuse hair loss.

14.1

Hair Shaft Defects Simulating Hair Loss

Hair shaft defects in children may cause fractures due to increased fragility of the hair shafts or they may present as irregularities along the hair shafts without increased breakage. Increased fragility may simulate hair loss and is found in, for example, trichorrhexis nodosa, congenital or acquired monilethrix, pseudomonilethrix, and pili

14

 

torti. These hair shaft anomalies are either associated with other clinical features or are isolated. Hair defects found in Netherton disease, Menkes disease or trichothiodystrophy present as specific syndromes of variable expression. In most cases, there is no causal therapy but genetic counseling of parents is necessary. However, defects of the hair shaft may also be acquired, as in acquired trichorrhexis nodosa, weathering or bubble hair. Reduction of repeated trauma to the hair shaft should result in normal regrowth of hair. Light microscopy of hairs longitudinally embedded in hair mount is a helpful diagnostic tool to identify the underlying hair shaft defect (Table 14.3).

14.1.1 Trichorrhexis Nodosa Congenita  

6

Synonyms trichorrhexis nodosa syndrome, Pollitt syndrome OMIM 275550, argininosuccinic aciduria OMIM 207900, biotinidase deficiency OMIM 253260

Table 14.3  Differential diagnosis of hair shaft defects with increased fragility in children (A): light microscopy and characteristic findings in longitudinally embedded hair in hair mount. (EM Electron microscopy, HI Histology, LM light microscopy, PLM polarizing light microscopy, TRG trichogram) see next page A Hair shaft defects with increased fragility Hair defect

Typical findings

Trichorrhexis nodosa

LM: Fracture with individual cortical cells and their fragments splaying out, resembles two brushes, whereby ends are pushed together

Monilethrix

LM: Uniform elliptical nodes and intermittent constrictions, so-called internodes, along the hair shaft

Pili torti and pili torti with copper deficiency in Menkes disease

LM: Closely grouped twists of flattened hair, twists are each 0.4–0.9 mm in width occurring in groups of 3–10 at irregular intervals along the shaft

Bamboo hair in Netherton syndrome

LM: Typical nodes resembling bamboo joints on longitudinal embedded hair, “cup portion” (proximal part), “ball portion” (distal part)

Trichothiodystrophy

PLM: Tiger-tail pattern LM: Irregular, slightly undulating contour, trichorrhexis-nodosa-like fractures with less release of individual cortical cells and clean, transverse fractures, trichoschisis

Ectodermal dysplasia

LM: Unspecific findings, pili torti may occur; HI: reduced number and hypoplasia of hair follicles and other appendage organs (sweat glands, sebaceous glands, etc.)

Weathering

LM: Bubble-like areas in the hair shaft (bubble hair), typical trichorrhexis nodosa fractures (see above), clean, transverse fissure or fracture through the hair shaft (trichoschisis), a shaft splinted in part by an intact cuticle, classic greenstick fracture (trichoclasis), longitudinal splitting of the hair shaft at its distal end leads to the common split ends (frizzies or trichoptilosis).

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Chapter 14

Table 14.3  (continued) Differential diagnosis of hair shaft defects without increased fragility in children (B): light microscopy and characteristic findings in longitudinally embedded hair in hair mount. (EM Electron microscopy, HI Histology, LM light microscopy, PLM polarizing light microscopy, TRG trichogram) B Hair shaft defects without increased fragility Hair defect

Typical findings

Pili annulati (syn.: ringed hair, pili anulati)

LM: Alternating bright and dark bands along the hair shaft. The bright appearance of the bands is due to air-filled cavities within the cortex that scatter the light. The colors of the bands are reversed when seen with reflected light. (Clinically, banding is seen only in blond or lightly pigmented hair)

Pseudo pili annulati

LM: With transmitted unpolarized light, variations in fiber diameter due to twisting of the oval hair about its long axis are found (the internal structure is entirely normal). PLM: with crossed polarizers and retardation plate, alternating segments of color, i.e., a blue segment followed by a yellow segment are found. (Clinically, banding is seen only in certain positions in blond hair)

Woolly hair

LM: Ovoid or elliptical cross-sections, 180º axial twisting of the hair shaft. Anagen hair bulb is commonly lacking a root sheath, but anagen:telogen ratio is normal. Weathering, trichorrhexis nodosa or lacking of cuticles may be found

Pili trianguli et canaliculi (syn. : uncombable hair, spun glass hair, cheveux incoiffable, Struwelpeter)

LM: May be normal. PLM: Changing alignment of hair shafts EM: Longitudinal grooves and triangular or kidney-shaped cross-sections

Pili bifurcati

LM: Hair shaft separates to form two parallel branches, each vested with a complete circumferential cuticle, then the branches fuse again to form a single hair shaft. Splitting and fusing occurs within irregular intervals along the hair

Pili multigemini

Biopsy of the scalp: two to eight matrices and dermal papillae with all hair shafts emerging from one single pilosebaceous canal. Each hair is formed by a single branch of dermal papilla which is surrounded by all layers present in normal follicle except for the outer root sheath cells

Twisted and rolled body hairs with multiple, large knots

LM: Central sticking and knotting of numerous hairs, resulting in one large knot

Acquired progressive kinking of the hair

Clinically, tight, short and curly hair in an otherwise normal scalp appears in circumscribed regions, usually in the frontal and temporal areas with an unruly and rough appearance. Occasionally, all scalp hair may be involved. Affected hairs may be thinner or coarser than in the unaffected scalp regions and hair color darker than normal

14.1.1.1

Introduction

Trichorrhexis nodosa is not specific for a disease, but represents an important diagnostic clue to a possible underlying metabolic disorder. In congenital trichorrhexis nodosa, the hair shaft fragility is often the only abnormal clinical feature. Occasionally, other ectodermal defects can be associated.

14.1.1.2

History

In 1952, Rousset reported about a family with trichorrhexis nodosa and associated defects of teeth and nails [70]. Later on in 1958, Allan and co-workers discovered the association to argininosuccinicaciduria [70]. The term “nodosa” is used primarily for historical reasons. It refers to the node which is sometimes seen with the naked eye at the site of this defect.

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14.1.1.3

14

Epidemiology

 

Trichorrhexis nodosa is the most common defect of the hair shaft. In general, trichorrhexis nodosa is often found in patients complaining of increased fragility of hairs.

nosuccinic acid. The hair defect may also be present in biotinidase deficiency, an inborn or acquired error of biotin uptake [107]. In zinc deficiency, clinical features resemble those of acrodermatitis enteropathica [87]. However, other syndromes including ectodermal defects are occasionally associated [49].

14.1.1.4

14.1.1.6

Pathogenesis

Pathology

Trivial trauma to the hair shaft and an inherent weakness of the hair shaft result in trichorrhexis nodosa congenita. The earliest observed change is a localized loss of cuticle cells. The exposed cortical fibers later separate and fray, causing a nodular swelling of the hair shaft. Trichorrhexis nodosa congenita without associated defects is rare. In addition, it may also appear in genetic syndromes such as Netherton syndrome, Tay syndrome, Basex-Dupré-Christol Syndrome and Menkes disease. Trichorrhexis nodosa syndrome, also called Pollitt syndrome, is a form of non-photosensitive trichothiodystrophy. Trichorrhexis nodosa also occurs in metabolic disorders such as biotin and zinc deficiency, or in argininosuccinicaciduria, an autosomal-recessive disorder of the urea cycle. Urea cycle disorders are characterized by the triad of hyperammonemia, encepha­ lopathy, and respiratory alkalosis. Trichorrhexis nodosa has been recorded in hypothyroidism [55].

In light microscopy, individual cortical cells and their fragments are splayed-out. The defect resembles two brushes with their ends pushed together (Fig. 14.1a,b).

14.1.1.5

In trichorrhexis nodosa, mild cosmetic procedures are recommended to decrease trauma of fragile hair. In argininosuccinase deficiency, a low-protein, argininesupplemented diet may reverse hair shaft fragility. Early treatment of partial argininosuccinate lyase deficiency may result in normal intellectual and psychomotor development. In biotin deficiency 5 mg biotin per day and in zinc deficiency supplementation of, e.g., 40 mg zinc daily may resolve clinical symptoms [87, 107]. In the case of hypothyroidism, substitution is mandatory.

Clinical Features

In trichorrhexis nodosa congenita, the hair often appears normally thick and long at first, but becomes fragile in the first year. The abnormal fragility becomes evident as the hair breaks, leaving variable lengths of broken hair and even partial alopecia. Trichorrhexis nodosa is also found in infants with argininosuccinicaciduria. The onset of symptoms of argininosuccinicaciduria occurs during the first weeks of life. Features include mental and physical retardation, convulsions, episodic unconsciousness, liver enlargement, skin lesions, and dry and brittle hair showing trichorrhexis nodosa microscopically and fluorescing red. In comparison to classic cases, variant cases of argininosuccinate lyase deficiency and argininosuccinic acid synthetase deficiency have been reported. In affected individuals, symptoms may present at birth, within the first months until the second year of life. Lethargy, seizures, respiratory distress at birth or gradual onset of physical, mental retardation, hepatomegaly and ataxia vary depending on the clinical form of argininosuccinicaciduria [22]. Laboratory testing reveals acidosis, hyperammonemia, low serum arginine, elevated serum and urine citrulline and argini-

14.1.1.7

Differential Diagnosis

In trichorrhexis nodosa, acquired forms should be differentiated from congenital forms and associated features. Mainly, trichorrhexis nodosa is acquired and traumatic cosmetic procedures are identified. On clinical inspection, in trichorrhexis invaginata multiple, small nodules are seen along the hair shaft as in trichorrhexis nodosa. To separate trichorrhexis invaginata from trichorrhexis nodosa, embedding of the hair shaft in hair mount will reveal the typical features of bamboo hair.

14.1.1.8

Treatment

14.1.2 Monilethrix  

6

Synonyms Beaded hair OMIM 158000 and 252200

14.1.2.1

Introduction

Monilethrix is a rare, hereditary hair shaft anomaly in which affected fragile hairs have a unique beaded morphology.

Hair Loss in Children

Chapter 14

279 Fig. 14.1a,b  Trichorrhexis nodosa resembles two brushes with their ends pushed together (a light microscopy; b scanning electron microscopy)

14.1.2.2

History

In 1879, Walter Smith described a rare nodose condition of the hair, later known as monilethrix. Due to its distinct morphology resembling a pearl necklace the name derived from the Latin word “monile” (necklace) and the Greek word “thrix” (hair).

14.1.2.3

Epidemiology

Expression of monilethrix is variable: in mild cases, dystrophic hair may be confined to the occiput but more severely affected individuals have near total alopecia. Extensively affected kindred with a pattern of dominant inheritance have been reported [50]. However, some families might have a recessive form of the disorder [83].

14.1.2.4

Pathogenesis

Monilethrix, an autosomal-dominant human hair disorder, is caused by mutations in three type II hair cortex keratins and chromosome 12 q13 [89]. The three hair keratin genes encode the type II hair keratins Hb1, Hb3, and Hb6, which share a completely identical α-helical

rod domain and, in line with the ultrastructurally observed disease symptoms, are all expressed in the hair cortex [50]. Rare cases of the disease with non-vertical transmission have now been found to overlap with localized autosomal-recessive hypotrichosis. The underlying gene, desmoglein 4, belongs to the desmosomal cadherin superfamily and is also expressed in the cortex of the hair follicle [83].

14.1.2.5

Clinical Features

Vellus hair is usually present at birth but is soon replaced by dry, brittle and lusterless moniliform hairs. The beaded hair emerges from keratotic follicular papules, breaks spontaneously almost flush with the scalp or obtains a maximal length of 0.5–2.5 cm leading to various degrees of alopecia. In the mildest form, the disease involves only the occiput and the nape of the neck, but in its severe form, the entire scalp, hair of eyebrows and eyelashes, facial pubic and axillary hair, and the hair of the arms and legs may also be affected. Follicular keratosis is associated in affected areas, predominantly on the scalp. In rare cases nail defects (koilonychia), cataract or mental retardation have been found in children with monilethrix [29] (Fig. 14.2).

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Fig.  14.3  Monilethrix: Uniform regular nodes and intermittent constrictions (internodes #) along the hair shaft are found in light microscopy

Fig.  14.2  Monilethrix in a 16-year-old girl. Typical finding of erythematosus papules, follicular keratosis and broken off hairs with various length in the occipital region

14 14.1.2.6

Pathology

Light polarizing microscopic examinations reveal characteristic uniform nodes and intermittent constrictions (internodes) along the hair shaft. Hairs show regularly spaced fusiform, spindle-shaped or elliptical swellings. The nodes are the normal diameter of the shaft and the internodes represent atrophic parts. Trichorrhexis with broken-off ends may also be seen due to increased fragility of the hair (Fig. 14.3).

14.1.2.7

Differential Diagnosis

Pseudomonilethrix and pili torti should be considered as differential diagnoses. Mainly developing from the age of 6–8 years on, these hair shaft anomalies present mostly without total alopecia, with brittle, fragile hair varying in length from 1 to 4 cm over the occiput and from 10 to 12 cm over areas less exposed to friction. In addition, their features in light microscopy differ to those seen in monilethrix. In pseudomonilethrix, the nodes are irregularly spaced and the internodes represent the normal hair shaft caliber. In pili torti, twists with an angle at about 180º along the hair shaft are found.

14.1.2.8

Treatment

Avoidance of hair trauma is a major principle in the management and counseling of the patient. However, oral acitretin may improve clinical conditions, but symptoms recur after discontinuation [47]. Occasionally, regrowth of apparently normal hair may occur at the time of puberty or during pregnancy [12].

14.1.3 Pseudomonilethrix  

6

Synonyms pseudo-monilethrix OMIM 177750

14.1.3.1

Introduction

Pseudomonilethrix has been classified in three different types: I, familiar pseudomonilethrix of BentleyPhillips (autosomal-dominant inheritance); II, acquired pseudomonilethrix in dysplastic disorders with hair fragility (inheritance profile depending on the dysplastic disorder); and III, iatrogenic pseudomonilethrix [30].

14.1.3.2

History

It was first described by Bentley-Phillips and Bayles [12] in 1973 and clinically affects the whole scalp as a generalized hypotrichosis or just the occipital area. The

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Chapter 14

281

term was chosen to indicate the resemblance to classical monilethrix.

14.1.3.3

Epidemiology

Pseudomonilethrix is a rare dysplastic disorder of the hair shaft that is inherited as an autosomal-dominant trait with high penetration but variable expressivity.

14.1.3.4

Pathogenesis

Fig.  14.4  Irregularly spaced nodes and internodes along the hair shaft in light microscopy are found in pseudomonilethrix

Pseudomonilethrix, a developmental hair shaft defect, is characterized by irregular nodes along the hair shaft, with fragility and breakage of hair resulting in partial baldness. Due to spontaneous breakage of the hairs, varying degrees of alopecia only involving the scalp are seen. However, artifactual induction should be excluded. As yet no specific pathogenetics are known.

14.1.3.8

14.1.3.5

14.1.4 Pili Torti

Clinical Features

Pseudomonilethrix may start in the first months of life, although, in some cases, it does not become apparent until childhood. Hair is dry, brittle, irregular in length and difficult to groom. No follicular papules can be seen on physical examination. In children with acrodermatitis enteropathica and reduced hair density pseudomonilethrix may be found [30].

14.1.3.6

Pathology

The hallmark of pseudomonilethrix can be observed by light microscopy, as nodes 0.75–1 mm in length interrupt the hair at irregular intervals. Internodes are of normal hair shaft thickness. Using magnifications up to 3000× in electron microscopy, the “nodes” appear to be an optical illusion. Actually, the hair is indented at these regions, as the sides of the indentation protrude beyond the normal diameter of the shaft. Irregular twists of 25º–200º without flattening of the shaft can be observed. Essentially, scales are normal along the whole hair shaft (Fig. 14.4).

14.1.3.7

Differential Diagnosis

Monilethrix has to be differentiated by light microscopic examination, showing regular nodes and internodes in contrast to irregular nodes in pseudomonilethrix. In contrast to monilethrix, neither keratosis pilaris nor any other associated defects have yet been reported.

Treatment

The avoidance of trauma is the most effective method of managing this hair anomaly.

 

6

Synonyms pili torti OMIM 261900, pili torti and nerve deafness, Björnstad syndrome OMIM 262000, twisted hair, corkscrew hair

14.1.4.1

Introduction

Pili torti show a distinct hair shaft anomaly with increased fragility and can be classified into two groups: a classic early-onset Ronchese type and a late-onset Beare type. In addition, pili torti can be associated with copper deficiency (e.g., in Menkes disease) or with ectodermal defects and syndromes (e.g., Crandall’s or Björnstad syndrome).

14.1.4.2

History

Pili torti were first discussed in the context of monilethrix by Schutz in 1900 [80]. Later on, Ronchese described congenital pili torti in detail [4].

14.1.4.3

Epidemiology

Pili torti may be congenital, sporadic or acquired. Congenital pili torti may be isolated or in association with other abnormalities and syndromes. Classic pili torti is

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more common in females, primarily those with thin blond hair. The hair may be abnormal from birth or it may become abnormal in the early years of life. In earlyonset pili torti, the pattern of inheritance is variable, and both autosomal-dominant and automsomal-recessive forms have been reported. The late-onset Beare type tends to manifest as patchy scalp alopecia after puberty. It presents as an autosomal-dominant condition [4]. Other defects have been reported in association with pili torti, as in Basex syndrome, Rapp-Hodgkin hypohidrotic ectodermal dysplasia, Menkes syndrome and familial acne conglobata. Pili torti have been sporadically found in other hair shaft anomalies such as monilethrix, pseudomonilethrix, woolly hair, longitudinal groves, trichorrhexis nodosa, and trichorrhexis invaginata.

14.1.4.4

Pathogenesis

Possibly, a fault in the inner root sheath impairs the molding of the growing hair shaft, leading to twisting of the hair. Taking into account that axillary and pubic hair are normally twisted and associated symptoms and defects are variable in pili torti, the underlying patho­ mechanism remains obscure.

14

14.1.4.5

Clinical Features

In classic pili torti (Ronchese) the hair is fragile, breaks easily and alopecia starts on the temporal and occipital areas, occasionally affecting eyebrows and lashes. Lateonset Beare type presents with spangled, dry, brittle hair that breaks at different lengths and may stand out from the scalp. The hair tends to be short, especially in areas subject to trauma. Classic pili torti may also be part of an ectodermal dysplasia syndrome, associated with keratosis pilaris, widely spaced teeth, nail dystrophy, corneal opacities, cleft lip palate, and occasionally ichthyosis. Other defects have been reported with pili torti: facial deformities, syndactyly of digits, mental retardation and also palagonia type of acrofacial dysostosis with oligodontia, normal intelligence, syndactyly, attenuation of 4th metacarpals, short stature, cleft lip, and vertebral anomalies [85]. In some pedigrees with late-onset type [9], mental retardation was present. In a number of patients sensorineural loss of hearing (cochlear type) has been reported in association (Björnstad syndrome). The latter emphasizes the importance of early auditory testing in children with this hair structure defect. Moreover, pili torti and sensorineural deafness are found together with hypogonadism in Crandall’s syndrome. So-called corkscrew hair, a variant of pili torti, has been described

 

Fig.  14.5  Light microscopy of pili torti showing a flattened hair shaft twisted through 180° on its longitudinal axis

in association with widely spaced teeth and syndactyly of fingers and toes. Acquired pili torti are mainly localized or patchy and are due to repetitive trauma. Pili torti are found in cicatricial alopecias of various origins, possibly due to distortion of the hair follicle caused by fibrosis.

14.1.4.6

Pathology

In light microscopy of pili torti, a flattened hair shaft twisted through 180º on its own longitudinal axis is found. Twists are found irregularly along the hair shaft. The phenomenon of many hairs twisted in a double spiral is called corkscrew hair (Fig. 14.5).

14.1.4.7

Differential Diagnosis

Isolated twisted hairs are also seen in normal scalps. In pili torti, these hairs are present at a remarkably high number and density. Monilethrix is often confused with pili torti, since irregular torsions along the hair shaft resemble the moniliform appearance. In addition, pili torti could indicate a carrier status for the Menkes disease gene. Moore and Howell [61] found pili torti in all affected males and in 43% of 28 obligate carriers or females at risk. Pili annulati should be differentiated in light microscopic analysis. Light and dark bands are seen along the hair shaft without twisting. This hair shaft anomaly does not cause increased fragility, but a distinct appearance of the hair with intermittent light and dark bands. Pili annulati, or ringed hair, may also be found in woolly hair. Children present with curled hair which is difficult to comb. In children with spun glass hair or uncombable hair, pili trianguli et canaliculi are found and may be confused with pili torti. Characteristic findings are triangular or kidney-shaped hairs seen in crosssections and longitudinal grooves which are responsible for the frizzy, stand-away appearance of uncombable hair (Fig. 14.6a,b, Table 14.3).

Hair Loss in Children

Chapter 14

14.1.5  

283

Menkes Disease

6

Synonyms Menkes syndrome, kinky hair disease, Steely hair disease, copper transport disease OMIM 309400

14.1.5.1

Introduction

Menkes disease is a highly lethal, X-linked recessive disorder of copper metabolism dominated by neurodegenerative symptoms and connective tissue disturbances presenting hair with increased fragility due to pili torti.

14.1.5.2

History

Pili torti with copper deficiency was first described by Menkes [59] and colleagues in 1962. In 1988, Menkes listed six cuproenzymes, five of which may account for features of the disorder: tyrosinase for depigmentation of hair and skin pallor; lysyl oxidase for frayed and split arterial intima (defect in elastin and collagen cross-linking); monoamine oxidase for kinky hair; cytochrome c oxidase for hypothermia; and ascorbate oxidase for skeletal demineralization. Dopamine-beta-hydroxylase is also a cuproenzyme; what role its deficiency may have in the phenotype of kinky hair disease is unclear [59].

14.1.5.3

Epidemiology

In Menkes disease, an X-linked recessive disorder of copper metabolism, the incidence is estimated at about 1 patient per 254,000 live-born babies in Europe [94]. In Asia, the incidence of live-born patients has been reported to be 2.8 per million live births and 4.9 per million male live births [38]. Fig.  14.6  a Typical frizzy and stand-away appearance of uncombable hair in a 6-year-old girl; b characteristic pili trianguli et canaliculi in scanning electron microscopy

14.1.4.8

Treatment

With regard to the hair shaft anomaly, the condition often improves over a number of years, particularly after puberty. There is no causative treatment of pili torti. Patients should be advised to minimize trauma to the fragile hair.

14.1.5.4

Pathogenesis

Menkes disease is an infantile neurodegenerative disorder caused by mutations in ATP7A, an X-chromosomal gene that encodes a copper-transporting P-type ATPase. Recent findings support the localization of the Menkes locus (MNK) to Xq13, with a suggested fine mapping to sub-band Xq13.3 [98]. Deficiency of the ATP7A gene product results in abnormal cellular copper transport and reduced activities of numerous copper-dependent enzymes. Deficiency of lysyl oxidase, a copper enzyme involved in extracellular matrix metabolism via oxidation of lysine residues in elastin and collagen, may cause

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Natalie Garcia Bartels, Ulrike Blume-Peytavi

generalized vascular tortuosity in patients with Menkes disease [35].

14.1.5.5

Clinical Features

Affected infants may develop normally until the onset of symptoms, usually between the age of 5 weeks and 5 months. Patients show characteristic white, steely, hair and neurological symptoms, such as seizures, delayed development, and muscular hypotony [13]. In Asians, hair color may also be brown or blond. Bony changes, resembling scurvy, tortuosities of the cerebral and systemic vasculature, and diverticuli of the bladder are also seen.

14.1.5.6

14.1.5.7

Differential Diagnosis

The recognition of Menkes disease may present problems in the early neonatal period. The serum copper and caeruloplasmin levels may be within the range of normal infants in the first week of life; they are higher than normal in the cord blood of affected infants and fall gradually after 4 weeks of age. Pili torti may develop later, as the primary fetal hair is usually normal. The baby may appear bald, or both normal and abnormal hair may be found in different areas of the skull. The roentgenographic signs may not be evident until after 6 weeks of age. Menkes disease should be included in the differential diagnosis of unexplained rib and metaphyseal fractures, subdural hematomas, and neurological impairment in infants where the diagnosis of non-accidental injury such as that seen in the shaken baby syndrome is considered [63]. Other causes of epilepsy should be excluded. Bony changes resembling scurvy and vascular defects offer a broad spectrum of underlying diseases.

14.1.5.8

tempts with parenteral administration of copper-histidine complexes have been made, with rather discouraging results. However, when copper-histidine complexes are supplied before manifestation of neurological or developmental defects, prognosis can be influenced to a certain extent [97]. Copper-histidine treatment bears the potential risk of copper overload and induced liver cirrhosis.

14.1.6 Netherton Syndrome  

6

Synonyms Netherton disease, Netherton syndrome, Netherton’s syndrome, bamboo hair OMIM 256500

Pathology

In light microscopy, characteristic features of pili torti are found. The most diagnostic alteration is a marked reduction in blood copper and caeruloplasmin levels. Markedly decreased copper levels are also found in the brain and liver of affected boys. Computed tomographic angiography is an accepted method for delineation of aneurysms, a possible feature in Menkes disease.

14

 

Treatment

The prognosis is poor and most of the patients die within the first 3 years of life. Various therapeutic at-

14.1.6.1

Introduction

The term “bamboo hair” refers to a distinctive hair shaft abnormality found in a rare syndrome, termed Nether­ ton syndrome, which combines ichthyosiform skin changes, mainly consistent with ichthyosis linearis circumflexa Comèl and frequently an atopic state. In addition, erythroderma present at birth may also be found in association with the disease.

14.1.6.2

History

Ichthyosis linearis circumflexa was first described by Dr Comèl in 1949. It consists of migratory polycyclic erythematous patches surrounded by a serpiginous overlying double-edged scale. Patients report migration of erythema as much as 0.5  mm/day. In 1958, Dr EW Netherton described the bamboo-like deformity in the fragile hairs of a girl with erythematous scaly dermatitis. Netherton syndrome has evolved with observation of patients to include the triad of trichorrhexis invaginata, ichthyosis linearis circumflexa, and an atopic diathesis. Confusion has developed regarding patients who appear to have ichthyosis linearis circumflexa alone; however, trichorrhexis invaginata is a necessary finding in the diagnosis of Netherton syndrome [27].

14.1.6.3

Epidemiology

This rare disorder is inherited in an autosomal-recessive fashion. A dispute over gender predominance exists, with the thought that girls are much more commonly affected than boys, but Smith and co-workers showed 20 out of 44 cases to be male [88]. The incidence of Netherton syndrome is estimated to be 1 in 200,000. Netherton

Hair Loss in Children

syndrome is also thought to be the cause of up to 18% of congenital erythrodermas. The hair defect appears in infancy within the first 3 years of life and affects all hair to a certain degree [88].

14.1.6.4

Pathogenesis

Available evidence suggests that the defect is located on chromosome 5q32 [19]. Recently, SPINK5, which encodes the serine protease inhibitor Kazal-type 5 protein (LEKTI), has been identified as the defective gene in Netherton syndrome [10].

14.1.6.5

Clinical Features

Trichorrhexis invaginata causes patchy hair thinning, but sometimes complete alopecia. The remaining scalp hair has a dry, lusterless appearance. Eyelashes and eyebrows are sparse or absent. Ichthyosiform erythroderma may be present at birth or can develop within the first few weeks postpartum. A collodion membrane is rarely present at birth. Most children are affected with ichthyosis linearis circumflexa and generally show a normal development (Fig. 14.7). However, patients with erythrodermic Netherton syndrome often fail to thrive and suffer from hypernatraemia, hypothermia, recurrent infections, and septicemia, resulting in high postnatal mortality. The initial erythroderma usually evolves into ichthyosis linearis circumflexa over time. Patients also have features suggestive of atopic dermatitis with

Fig.  14.7  Ichthyosis linearis circumflexa on the hand of a 7-year-old girl

Chapter 14

erythema and lichenification at flexural creases and diffuse generalized xerosis. In addition, mental deficiency, neurologic deficits (either seizure disorders or spastic diplegia), delayed growth and body development, short stature, recurrent infections (skin, eye, upper or lower respiratory tract), and hypogammaglobulinemia or hypergammaglobulinemia have been reported in affected individuals.

14.1.6.6

Pathology

Findings in light microscopy compromise one or more nodes or nodular fractures, irregularly distributed along the affected shafts. The abnormal, tulip like invagination along the shaft is responsible for the extreme fragility of the hair, not allowing the hair to reach its normal length (Fig. 14.8a,b). In some cases, the pathological findings

Fig. 14.8a,b  In Netherton Syndrome a tulip-like invagination with “cup and ball” portion along the shaft demonstrated by (a) light microscopy and (b) scanning electron microscopy

285

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Natalie Garcia Bartels, Ulrike Blume-Peytavi

are more prominent in vellus hairs than in terminal scalp hairs. Typical ultrastructural findings in histology are suppression of cornification characterized by the absence or massive reduction of keratohyalin granules, decrease of keratin filaments and premature exocytosis of lamellar bodies in the intercellular spaces of the stratum corneum.

14.1.6.7

Differential Diagnosis

Trichorrhexis invaginata is considered to be patho­ gnomonic in Netherton syndrome, but may be difficult to detect in infancy and early childhood. Differential diagnoses include generalized seborrheic dermatitis, erythrodermic psoriasis, congenital non-bullous ichthyosiform erythroderma, and staphylococcal scalded skin syndrome (SSSS). Congenital ichthyosis, erythrodermic psoriasis or generalized seborrheic dermatitis can be excluded based on histology. In addition to its histological features in SSSS, bacteriological skin smears are negative.

14.1.6.8

14

Treatment

Patients with Netherton syndrome are likely to be more susceptible to systemic absorption of medication, and are therefore at increased risk of experiencing adverse reactions to topical therapies. Exfoliative erythroderma and hypernatremic dehydration with an increase of serum levels of urea after local treatment with an ointment containing 5% urea, 5% NaCl and 5% lactate four to five times daily has been reported. Case reports highlight significantly elevated serum tacrolimus levels in children with Netherton syndrome. Use of tacrolimus ointment in patients with Netherton syndrome should be reserved for the short-term management of flares on a limited body surface area and should be considered only when the benefits clearly outweigh the risks [82]. A crucial point in topical therapy is an intensive skin care of application of hydrophobic creams without additives or with a low dose of urea, for treating only specific parts of the body surface daily. Systemic administration of retinoids is discussed controversially in the literature, but might be beneficial when older and particularly in milder forms. The oral retinoid therapy may not heal the basic defect, but keratinization seems to normalize and hair can clinically improve. In addition, hair growth may improve with age [62].

 

14.1.7 Trichothiodystrophy  

6

Synonyms Ichthyosiform erythroderma with hair abnormality, mental and growth retardation, trichothiodystrophy with congenital ichthyosis, Tay syndrome, photosensitive trichothiodystrophy (TTDP), BIDS (Amish brittle hair brain syndrome, TTDN1), IBIDS or PIBIDS syndrome OMIM 601675

14.1.7.1

Introduction

Trichothiodystrophy (TTD) refers to a heterogeneous group of autosomal-recessive disorders that share the distinctive features of short, brittle hair and abnormally low sulfur content [73].

14.1.7.2

History

In two brothers and a sister, with first-cousin parents of Chinese extraction, Tay [93] described in 1971 a new autosomal-recessive disorder characterized by nonbullous ichthyosiform erythroderma, growth and mental retardation, somewhat progeria-like appearance, and short, sparse, lusterless hair that microscopically showed pili torti and trichorrhexis nodosa. Trichothiodystrophy (TTD) is a term introduced by Price and co-workers in 1980 [73] for sulfur-deficient brittle hair and associated symptoms.

14.1.7.3

Epidemiology

Within the spectrum of the TTD syndromes, numerous interrelated neuroectodermal disorders exist. Abnormalities in excision repair of ultraviolet- (UV-) damaged DNA are recognized in about half of the patients.

14.1.7.4

Pathogenesis

Three distinct autosomal-recessive syndromes are associated with nucleotide excision repair (NER) defects: the photosensitive form of TTD, xeroderma pigmentosum, and Cockayne syndrome. Genetically, three complementation groups have been characterized among photosensitive patients with TTD. Most patients exhibit mutations on the two alleles of the XPD gene. Mutated XPB gene or an unidentified TTD-A gene rarely results in TTD. In UV-sensitive TTD, the TFIIH transcription factor containing XPB and XPD helicase activities, nec-

Hair Loss in Children

essary for both transcription initiation and DNA repair, is damaged [46]. Recently, C7orf11 (TTDN1) was identified as the first disease gene for the non-photosensitive form of TTD, being mutated in two unrelated cases and in Amish kindred [16]. Hair of affected patients shows shaft abnormalities such as trichoschisis, trichorrhexis nodosa, or ribbon/twist, which is inversely correlated to the sulfur content of the hair. Raman spectra of hairs from TTD patients and normal donors show that there is a higher contribution of energetically less favored di­ sulfide conformers in TTD hairs. These changes make TTD hairs excessively prone to breakage and weathering [54].

14.1.7.5

Clinical Features

Patients with TTD share the distinctive feature of short, brittle hair. The presence of low sulfur content in hairs and one of trichoschisis, tiger-tail pattern by polarizing light microscopy or severe cuticular damage by scanning electron microscopy are mandatory for diagnosing TTD. Persistent alopecia of the scalp is often found; eyebrows, eyelashes and body hair may also be affected. Associated clinical symptoms include physical and mental retardation of different severity, nail and dental dysplasias, cataracts, ichthyosis, premature aging, and, in half of the patients, photosensitivity. TTD syndromes include BIDS (brittle hair, intellectual impairment, decreased fertility, short stature), IBIDS (ichthyosis and BIDS), and PIBDS (photosensitivity and IBIDS).

14.1.7.6

Pathology

The hair has markedly low sulfur (cystine) content and presents characteristic light and polarizing features, the so-called tiger-tail pattern: alternating light and dark bands (Fig. 14.9). This characteristic pattern may be absent at birth and in the neonatal period. However, in biopsy samples of fetal eyebrows, lower cystine levels

Chapter 14

(19 µm/l) compared to age-matched control (368 µm/l) can be found at the second trimester [75]. In addition, trichorrhexis-nodosa-like fractures or trichoschisis may be found.

14.1.7.7

Differential Diagnosis

Trichothiodystrophy has a broad spectrum of differential diagnoses since various clinical features are associated. Mainly, forms of erythrodermic ichthyosis, collodium baby and progeroid syndromes should be considered. Xeroderma pigmentosum, Cockayne syndrome and TTD share increased photosensitivity and display severe progeroid symptoms. Although caused by defects in genome maintenance via the nucleotideexcision, DNA-repair pathway, Cockayne syndrome and TTD patients appear to lack any cancer predisposition. In Cockayne syndrome, “cachectic dwarfism” describes the outward appearance of afflicted individuals. Other features include cutaneous photosensitivity, thin dry hair, a progeroid appearance, progressive pigmentary retinopathy, sensorineural loss of hearing, dental caries, and a characteristic “horse-riding” stance. Primarily, the distinct hair pathology presenting with tiger-tail pattern or trichoschisis together with its low sulfur content is the key to identifying TTD.

14.1.7.8

Treatment

In contrast to patients with xeroderma pigmentosum, no increase in skin cancer in patients with TTD has been observed. However, early prevention of sun-induced skin damage is necessary in photosensitive patients. Dietary cytosine supplementation has been suggested, but its value is unproven.

14.1.8 Ectodermal Dysplasia  

Synonyms OMIM NA

14.1.8.1

Fig. 14.9  Trichothiodystrophy shows characteristic features in polarizing light microscopy: the “tiger-tail” pattern with alternating light and dark bands along the hair shaft

287

6

Introduction

Ectodermal dysplasias (EDs) represent a large and complex group of diseases comprising more than 170 different clinical conditions. Hair shaft anomalies are found in some cases, e.g., pili torti were reported in Crandall’s or Björnstad’s syndrome [23, 99]. In general, hair may be sparse, curly, and fair. Alopecia may be due to a hair

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shaft anomaly with increased fragility, or to hypotrichosis. Hair shaft anomalies such as pili torti are not specific for a certain subgroup of ectodermal dysplasias. Eyebrows or eyelashes may be sparse, malformed or absent.

14.1.8.2

History

The ectodermal dysplasias are a heterogeneous group of conditions primarily affecting the hair, teeth, nails, and skin, and are classified according to the tissue(s) affected. Several classifications of EDs have been already proposed: Pinheiro and Freire-Maia [67] reviewed EDs from a clinical point of view; Priolo et al. [74] integrated both molecular genetic data and corresponding clinical findings. In the light of the recent discovery of causative genes for EDs, a classification according to their function has been proposed by Lamartine [51].

14.1.8.3

14

Epidemiology

Ectodermal dysplasias are rare diseases with an estimated incidence of 7 out of 10,000 births for all EDs [58]. Of the 170 EDs described so far, fewer than 30 have been explained at the molecular level with identification of the causative gene [51].

14.1.8.4

Pathogenesis

Ectodermal dysplasias feature impaired development of ectodermal appendages. Their development is regulated by a sequence of inductive interactions between two adjacent tissue layers, the epithelium and the mesenchyme. Recent evidence implicates a genetic defect in different pathways, which orchestrate ectodermal organogenesis. Embryogenesis is regulated by a number of complex signaling cascades that are critical for normal development. One of the best investigated pathways is the sonic hedgehog, leading to interactions with the transcription factors within the Gli family. Dysregulation of the sonic hedgehog-patched gli pathway may lead to different diseases including some from the spectrum of EDs [74].

14.1.8.5

Clinical Features

Often, alopecia is a feature of subtypes in ectodermal dysplasias. Hair is generally fair and scanty, sometimes brittle and uncombable. Body hair is often diminished or absent. Eyebrows and eyelashes may be lacking. In general the skin is dry and fine.

 

From a clinical point of view, two main groups, specified as A and B, are helpful in looking for morphologic features in the child (Table 14.4, [45]). All entities having defects in at least two of the classical ectodermal structures such as hair, teeth, nails, and sweat glands belong to group A. Group B only has defects in one of the four above-mentioned structures, plus one other ectodermal defect, such as anomaly of ears, lips, or dermatoglyphics

Table 14.4  Clinical manifestations in ectodermal dysplasias. Group A: defects in at least two of the following ectodermal structures: hair, teeth, nails and sweat glands. Group B: defects in only one of the ectodermal structures hair, teeth, nail and sweat glands plus one other ectodermal defect, e.g., ears, lips, dermatoglyphics on palms and soles [45] Abnormalities in hair follicles Sparse, curly, and fair hair Alopecia because of hypotrichosis or increased hair fragility Eyebrows or eyelashes absent/sparse or malformed Dental changes Hypodontia or anodontia Malformed teeth with cone- or peg-shaped aspects Prone to caries because of enamel defect or salivary gland malfunction with xerostomia Nail changes Leukonychia Dystrophic and malformed nails Impaired sweat gland function Absence, reduction or increase of sweating Hyperthermia under warm conditions Skin alteration Superficial dry scaling skin at birth Dry and often hypopigmented skin Dermatitis resembling atopic skin disease Eye abnormalities Corneal dysplasias Cataract Displaced or stenotic lacrimal puncta Defective or decreased lacrimation

Hair Loss in Children

Chapter 14

Fig.  14.10  Ectodermal dysplasia type B. Abnormal shaped teeth

Fig. 14.11  Ectodermal dysplasia type B. Hyperkeratosis of the palms and soles, and bone anomalies (pes equinovarus, not shown)

on palms and soles (Figs. 14.10, 14.11). A disease which features only ectodermal signs is named a pure ectodermal dysplasia. A combination with other anomalies is named ectodermal dysplasia syndrome [45, 67]. The molecular classification of known genes causative of EDs and of their related diseases allows a genotype– phenotype correlation of these disorders. Another classification of EDs defines groups that are homogeneous and comparable from a clinical point of view, with respect to the molecular classification of causative genes. Several interactions among genes from different groups (especially groups II and IV) along common pathways of action have been noted [74]. Group I is composed of the so-called pure EDs, in which only epidermal derivative abnormalities are present. Identified causative genes are EDA1 and DL. Group II includes diseases characterized by premature aging. Identified causative genes are ERCC2, ERCC3 and RECQL4. Group III constitutes multiple congenital anomalies/EDs in which skeletal abnormalities are always present. Identified causative genes are p63, DLX3, TRPS1, and EVC. Group IV includes syndromic EDs characterized by premature aging and predisposition to neoplasias. The identified causative gene is DKC1. Group V diseases are all characterized by skin-associated disorders, such as keratoderma and skin fragility. Identified causative genes are KRT 16, KRT 6a, KRT 17, KRT 6b, PKP1, LOR, and CTSC. Members of the RecQ family (group II) are likely to be involved in normal telomere maintenance and cell aging. Dkc protein (group IV) is also involved in the same mechanisms. Accordingly, dyskeratosis congenita has several clinical features in common with Rothmund-Thomson syndrome, such as premature aging and predisposition to neoplasias. Based on these observations, it is clear that RECQ genes and DKC1 may interact in common pathways, thus explaining common clinical and biological

features. Four additional groups classifying the remaining diseases with different clinical features are: Group VI, with deafness as major clinical criteria; Group VII, with ocular anomalies/retinal dystrophy; Group VIII, with renal abnormalities; and Group IX, with associated endocrine–neuroendocrine abnormalities [74].

14.1.8.6

Pathology

Thorough clinical examination is mandatory to identify the underlying ED. Caused by impaired development of epidermal appendages, EDs are characterized by a primary defect in at least one of the following tissues: nails (dystrophic, hypertrophic, abnormally keratinized), hair (hypotrichosis, partial or total alopecia), teeth (abnormal or absent), and sweat glands (hypoplastic or aplastic). In some cases pili torti are found. They follow all possible Mendelian modes of inheritance (autosomaldominant or autosomal-recessive, X-linked dominant or recessive) but sporadic cases are also described.

14.1.8.7

Differential Diagnosis

A broad differential diagnosis is reflected by the different pathological conditions and clinical manifestations of EDs. In general, congenital hypotrichias and atrichias without other ectodermal defects should be considered.

14.1.8.8

Treatment

The prognosis and treatment depend on underlying defects, which are as heterogeneous as the group of EDs itself.

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14.1.9 Acquired Hair Shaft Defects with Fractures: Weathering  

6

Synonyms cuticular weathering OMIM NA

 

the twisted fibers of the beard and moustache as seen in chronic rubbing of these areas. In general, fractures of the hair shaft present as trichoschisis, trichoclasis or trichoptilosis.

14.1.9.5 14.1.9.1

Introduction

The term weathering is reserved primarily for all types of cosmetic manipulation, resulting in defects of the hair shaft. Hair consists of highly organized and orientated keratinized fibers and fibrils; and these can be modified by cosmetic procedures to give a variety of styles.

14.1.9.2

History

All through the ages, cosmetic procedures to change or enhance the outer appearance have been utilized. Hair in particular is a main target of modification, regarding quality, quantity, structure, and color.

14.1.9.3

14

Epidemiology

Depending on cultural aspects, hair styles differ worldwide in every country and population. However, repeated physical or chemical trauma of the hair shaft due to styling procedures may lead to hair defects with increased fragility.

14.1.9.4

Pathogenesis

In weathering, the damage to cuticular cells subsequently leads to loss of their cortex-protecting capacities and to breakage. In bubble hair, a reproducible cause has been established. Brief, focal heating of damp hair is sufficient to cause bubbles to form inside the hair fibers. This in turn results in weak, dry and brittle hair, which easily breaks. The most common cause of acquired hair fracture is trichorrhexis nodosa due to physical or chemical trauma. A contributory factor is an inherent weakness of the hair shaft. In the proximal type, some authors consider the excessive structural damage observed in African hair shafts is consistent with physical trauma (resulting from grooming) rather than an inherent weakness due to any structural abnormality. In contrast to the distal type, in the circumscribed type, a clear history of an underlying trauma is not always found. Frequent twisting and manipulation of the beard may be sufficient to break

Clinical Features

Bubble hair is characterized by weak, dry and brittle hair that breaks easily. Acquired trichorrhexis nodosa is found in the proximal or in the distal part of the hair shaft or maybe localized, as in patches of trichotillomania, lichen simplex chronicus or pruritic dermatoses [104]. Proximal trichorrhexis nodosa is mainly found in patients who are invariably Afro-American with a family history of short hair, but the genetic background is still under discussion. Distal trichorrhexis nodosa is seen primarily in Caucasians and Asians of both sexes. Both forms are acquired due to repeated trauma contributing to cuticular damage [14, 48]. Circumscribed trichorrhexis nodosa occasionally occurs in the scalp hair, moustache or beard, as a small patch.

14.1.9.6

Pathology

Bubble hair is characterized by bubble-like areas in the hair shaft seen with light microscopy and corresponding cavitary defects with scanning electron microscopy. Electron microscopy reveals a loss of cortical cells and medulla. Cross-section images showed either a single large cavity or a reticulated, “Swiss cheese-like” loss of cells. In trichorrhexis nodosa, hair mount shows broken segments of hairs and typical trichorrhexis nodosa fractures along the hair. Trichoschisis is a clean, transverse fissure or fracture through the hair shaft and localized absence of cuticle cells. A classic greenstick fracture is called trichoclasis, showing a shaft splinted in part by an intact cuticle. Longitudinal splitting of the hair shaft at its distal end leads to the common split ends, called frizzies or trichoptilosis (Fig. 14.12).

Fig. 14.12  In trichoptilosis, longitudinal splitting is found at the distal end of the hair shaft

Hair Loss in Children

14.1.9.7

Differential Diagnosis

In weathering, typical hair splitting at the hair tip or the upper hair is found. Depending on the cosmetic procedure not all hairs are affected, e.g., underlying hairs close to the scalp sometimes are less or not affected. In hair mount and light microscopy, pili torti, bamboo hair or monilethrix should be differentiated from trichorrhexis nodosa. Longitudinal embedding of hair shafts is helpful to identify the distinct hair shaft morphology in these hair defects. Bubble hair does not show a regular pattern like the tiger tile pattern in trichothiodystrophy using polarizing light. However, trichoschisis, trichoclasis or trichoptilosis is easily identified.

14.1.9.8

Treatment

In weathering, children and their parents should be advised to cease all chemical or physical hair manipulation. A wide-toothed, round-tipped comb or a soft brush is recommended. Hair conditioners are helpful and a cream rinse applied to the hair ends after shampooing minimizes tangling of the hair. Affected ends should be cut and hot hair dryers should be avoided completely.

14.2

Localized Hair Loss

Localized hair loss in children mainly presents as various degrees of non-scarring alopecia. However, in any type of localized hair loss a close inspection of the skin should be performed to differentiate between non-scarring or scarring alopecia. Inspection with dermoscopy of the scalp in affected areas is a non-invasive and easy tool to characterize the type of alopecia and detect early signs of scarring [78].

14.2.1 Non-Scarring Alopecia 14.2.1.1  

Alopecia Areata

6

Synonyms pelade, alopecia universalis OMIM 104000

14.2.1.1.1 Introduction Alopecia areata is a chronic inflammatory disease characterized by patchy, non- scarring hair loss with T-cell infiltration of hair follicles.

Chapter 14

14.2.1.1.2 History The first citation of alopecia areata is estimated about several decades Anno Domini. Later in 1706, Sauvages used the term “alopecia areata” in his Nosolgia Medica. Despite parasitic hypothesis in the nineteenth century, the autoimmune pathogenesis in genetically susceptible patients was established in the twentieth century [44].

14.2.1.1.3 Epidemiology Alopecia areata is a common cause of non-scarring hair loss in children mostly older than 3 years. In newborns and very young infants, however, it is thought to be rare [24]. It occurs in approximately 0.1% of the general popu­lation [79], but in approximately 9% of patients with Down syndrome [18].

14.2.1.1.4 Pathogenesis Substantial evidence indicates that genetic factors may have a role in the etiology of alopecia areata. In general, there is evidence of genetic heterogeneity in alopecia areata and its different clinical pattern [32, 100]. C3H/ HeJ mice spontaneously develop alopecia areata. Recent evidence suggests a major locus on mouse chromosome 17 and minor locus on chromosome 9 linked with alopecia areata in C3H/HeJ mice [90]. Fas-deficient C3.MRLTnfrsf6(lpr) mice do not develop hair loss, suggesting that the Fas pathway plays a pathogenetic role in alopecia areata [31]. However, the exact locus has not been identified (see Chap. 15).

14.2.1.1.5 Clinical Features Different degrees of non-scarring alopecia are found in patients with alopecia areata: round or oval patches (alopecia areata circumscripta, Fig. 14.13), complete alopecia of the scalp (alopecia areata totalis) or of the scalp and body hair (alopecia areata universalis), bandlike alopecia on the occiput (ophiasis-type), and rarely diffuse alopecia (diffuse-type). Atopic state (approx. 40%) and thyroid diseases (approx. 29%) are frequently found. Alopecia areata has also been associated with other autoimmune diseases, e.g., vitiligo, lupus erythematosus, rheumatoid arthritis, pernicious anemia, scleroderma, inflammatory bowel disease, myasthenia gravis, and lichen planus.

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creased telogen and dystrophic hairs in alopecia areata. In addition, triangular alopecia could be confused with patchy alopecia areata. Early stage of linear morphea can present as a single alopecic patch with very decent brownish macula without clinical evidence of scarring. If suspected, it should be excluded by histology.

14.2.1.1.8 Treatment According to clinical pattern, a poor prognosis may be estimated if alopecia areata occurs before puberty, a positive family history is given, more prolonged (> 2 years) and extended forms of the disease are present (alopecia areata totalis or universalis and ophiasis-type), there is nail involvement, and if associated autoimmune disorders are found. Depending on estimated prognosis and age the individual therapeutic concept should be established. For further details please see Chap.  15 on alopecia areata.

Fig. 14.13  Non-scarring alopecic patches in a 5-year-old boy with patchy alopecia areata

14.2.1.2  

14

14.2.1.1.6 Pathology The pull-test may be performed to evaluate the activity of the disease. In selective and unclear cases, a trichogram may help to exclude other causes of localized nonscarring hair loss. In acute cases, elevated rates of telogen and dystrophic hairs are found at the margin of the lesions. In difficult cases, histological evaluation may be performed showing a typical T-cell infiltrate, like a “swarm of bees,” around the bulb region.

14.2.1.1.7 Differential Diagnosis If the onset of complete alopecia is in infancy one should consider alopecia with papular lesions (APL) as the differential diagnosis. At birth, the hair usually appears normal on the scalp, but alopecia develops shortly after birth. A scalp biopsy shows few hair follicles, dilated and without hairs, and the absence of an inflammatory infiltrate. In patchy-type alopecia areata, other forms of localized, non-scarring alopecia should be taken into account. Most common is tinea capitis, showing scaling, sometimes erythema and pustules at the border of the lesion. Also, trichotillomania may be confused with alopecia areata. Trichogram reveals predominantly anagen hairs and nearly absent telogen hairs, in contrast to in-

Tinea Capitis

6

Synonyms trichophytosis superficialis capillitii, trichophytia profunda capillitii, kerion celsi, favus, dermatomycosis, OMIM NA

14.2.1.2.1 Introduction Tinea capitis is a dermatophytic fungal infection of the scalp that is particularly contagious among children.

14.2.1.2.2 History In 1841, Gruby reported the infectious etiology of tinea capitis; he cultured both the infectious agent causing favus and reproduced the condition by inoculation into a human subject [77].

14.2.1.2.3 Epidemiology Tinea capitis, a dermatophyte infection involving the hair shaft on the scalp, is primarily a disease of preadolescent children. The predominant pathogen varies according to the geographical location. Microsporum (M.) canis, Trichophyton (T.) tonsurans and T. audunii account for the majority of infections in certain parts of Europe and North America. Tinea capitis caused by M.

Hair Loss in Children

canis is a common mycosis of the scalp in children aged 1–3 years and 4–11 years [28].

14.2.1.2.4 Pathogenesis Common sources of infection by M. canis are cats, if they have had contact with infected cats in Southern European countries and guinea pigs. The pathogens colonize in the fur of the animals, often without causing apparent clinical symptoms. Transmission by indirect contact, i.e., with objects (car seats, stuffed animals, etc.) as well as person-to-person contact has also been reported. Hair invasion can occur as an ectothrix or endothrix infection. In ectothrix infections, the fungus, predominantly arthroconidia (spores), attaches to the surface of the hair shaft. In endothrix infections, the pathogen invades the hair shaft without destroying the cuticle. Typical pathogens involved in ectothrix infection are M. canis and M. audouinii as well as T. mentagrophytes var. granulosum. Endothrix infection can be caused by pathogens such as T. tonsurans or T. violaceum [81].

14.2.1.2.5 Clinical Features The clinical presentations are variable and include: (1) a “seborrheic” form that is scaling, often without noticeable hair loss; (2) a pustular, crusted pattern, either localized or more diffuse; (3) a “black dot” variety characterized by small black dots within areas of alopecia; (4) a kerion, which is an inflammatory mass [15]; and (5) a scaly, annular patch (Fig. 14.14). Favus is a specific type of tinea capitis characterized by scutula, which are sulfuric-yellow concretions of hyphae and skin debris at the orifices of hair follicles.

Chapter 14

293

14.2.1.2.6 Pathology Tinea capitis is diagnosed both clinically and using culture [68]. Clinical diagnosis of tinea capitis is confirmed by unstained specimens and fungal culture. The lesion is disinfected with 70% alcohol and any crusts are carefully removed using tweezers. Hair or hair stumps are plucked from the margin around the lesion. Examination using a Wood light (UV lamp, 365 nm UVA rays) can be useful for diagnosis, particularly with epidemic infections. Yellowish-green fluorescence confirms a diagnosis of Microsporum infection (e.g., M. canis). It should be noted that Wood light examination does not offer a particularly high degree of sensitivity for diagnosing M. canis infection of the scalp and, thus, is not a suitable means of excluding infection.

14.2.1.2.7 Differential Diagnosis Differentials include: psoriasis capitis, chronic contact eczema, atopic eczema, seborrhea capitis (after puberty), tinea amiantacea, alopecia areata, pyodermia, carbuncles, and occasionally, trichotillomania. However, cutaneous lupus erythematous and follicular lichen ruber are very rare in children.

14.2.1.2.8 Treatment Although the oral antifungal agents are the most important aspect of therapy, adjunctive topical therapy is beneficial. Sporicidal shampoos can aid in removing adherent scales and hasten the eradication of viable spores from the scalp in the hope of decreasing the spread of this infection. Mainly, alopecia is non-scarring and hair regrows after sufficient treatment. In rare cases of deep fungal infection a scarring alopecia may remain. Thus, early diagnosis and efficient treatment is important in tinea capitis. (For further details see also Chap. 19).

14.2.1.3  

Trichotillomania

Synonyms OMIM NA

6

14.2.1.3.1 Introduction Fig.  14.14  Non-scarring alopecic patch in a 3-year-old boy covered with white, fine scales. Tinea capitis was diagnosed by fungal culture revealing Microsporum canis infection

Trichotillomania (TTM) is an impulse disorder, in which patients chronically pull hair from the scalp and/or other sites complaining of lack of hair growth or of hair loss.

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14.2.1.3.2 History Trichotillomania derives from the Greek; trich (hair), tillo (pull) and mania (excessive excitement), as described by Hallopeau [77].

14.2.1.3.3 Epidemiology Very early onset of hair pulling in children under the age of 6 may be more benign and self-limiting than the more common syndrome of late-childhood-onset hair pulling. While far more women and adolescent girls appear for treatment, survey studies suggest that chronic hair pulling also occurs in males.

14.2.1.3.4 Pathogenesis Trichotilomania is found in patients who have an irresistible compulsion to pull out or twist and break off their hair. Patients often exhibit complex behavioral patterns as part of an obsessive-compulsive disorder or an impulse control disorder. Telogen hairs are plucked out with ease; anagen hairs may be plucked or twisted and broken off at various lengths.

14

14.2.1.3.5 Clinical Features Single or multiple nearly alopecic areas are found predominantly in the parietal and vertex regions (Fig. 14.15). Eyebrows, eye lashes, pubic hair, beard, and

 

body hairs are rarely affected. Sometimes these areas show a bizarre or geometric pattern. Close clinical inspection may reveal petechiae on the scalp close to follicle infundibulum or dark spots in the infundibulum. A number of hairs always remain in this area. In addition, onychophagia (nail-biting) may be associated.

14.2.1.3.6 Pathology Trichogram examination shows nearly 100% of anagen hairs and missing telogen hairs. In addition, broken hairs with blunted or frayed ends are seen. Biopsy specimen may reveal hair cast remnants at about 60%. Also, suggestive for diagnosis is a predominance of catagen hairs, since plucking induces a shift from anagen to catagen. Traumatized hair follicles may show trichomalacia and perifollicular hemorrhages.

14.2.1.3.7 Differential Diagnosis This entity can mimic the clinical appearance of many other forms of hair loss including alopecia areata, androgenetic alopecia, and tinea capitis. It is important to differentiate TTM from other forms of alopecia, because its treatment is quite different. Lack of telogen hairs showing nearly 100% of anagen hairs in the trichogram taken from the margin of the lesion is usually sufficient for differentiation. In rare cases, patients cut the hair leaving an area with short hair at a different length. This manipulation is called trichotemnomania, revealing a normal trichogram and clearly cut hairs in longitudinal embedded hairs.

14.2.1.3.8 Treatment Specialized age-adapted psychotherapy, such as habit reversal training, is recommended; however, the treatment is intensive and highly specialized [102].

14.2.1.4  

Fig.  14.15  An 11-year-old girl presented with a localized, non-scarring alopecia for >15 months. Trichotillomania was diagnosed after thorough clinical and psychological exploration and investigation. Psychological work-up succeeded in complete regrowth

Traction Alopecia

6

Synonyms traumatic alopecia, pony tail alopecia, OMIM NA

14.2.1.4.1 Introduction Traction alopecia is traumatic hair loss secondary to the application of tensile forces to scalp hair.

Hair Loss in Children

14.2.1.4.2 History Traction alopecia resulting from mechanical forces to hair has been in existence since the implementation of traditional methods of hair styling, but, to our knowledge, was first described in 1958 by Slepyan [86].

14.2.1.4.3 Epidemiology Traction alopecia is quite common in black children, especially with curly hair, due to traditional methods of hair styling [52]. Transient neonatal shedding and occipital alopecia is quite common in newborns within the first weeks of life.

14.2.1.4.4 Pathogenesis So far, the etiology of neonatal occipital alopecia has been reported to be friction. Recently, physiological shedding of hair in the first weeks of life has been identified as the cause of this phenomenon [25]. The pillow, which is often blamed, aids this shedding. Chronic traction of the hair may lead to transient alopecia. However, if continued over a period of time, permanent alopecia may develop due to atrophy of hair follicles.

14.2.1.4.5 Clinical Features This condition can be classified as marginal or nonmarginal. In neonates, circumscribed occipital hair loss is often found within the first weeks of life. Postnatal shedding and friction or pressure over the bony occipital prominence may contribute to this reversible phenomenon. In young girls, it may possibly be observed as “ponytail” alopecia, although traction may lead to loss of hair on any site of the scalp depending on the hairdressing techniques used. The clinical pattern of marginal alopecia or hypotrichosis in areas of chronic traction or friction frequently comprises mild perifollicular erythema. In some cases, chemical treatment of hairs in combination with friction leads to acute breakage of hairs, e.g., after use of agents to straighten hairs and combing of hair to a pony tail.

14.2.1.4.6 Pathology The diagnosis of traction alopecia is generally performed clinically. To exclude other underlying diseases, a trichogram or TrichoScan is helpful and should present relatively normal values in traction alopecia. In

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chronic traction alopecia, a reduced numbers of hair follicles, sometimes with fibrous tracts, may be seen in scalp biopsy samples.

14.2.1.4.7 Differential Diagnosis In neonates, non-marginal occipital alopecia may also be due to physiological hair shedding occurring 8–12 weeks postnatally. Different patterns of transient neonatal hair loss have been identified [25]. Marginal, often band-like, alopecia of the fronto-temporal region of the scalp may be confused with alopecia areata. In the latter case, the pull-test is positive. After traumatic injury to the scalp resulting in deep wounds, a cicatricial alopecia may result. Traumatic scarring lesions may occur due to accidents, burns, radiation or may be chemically induced [36, 105]. In loose anagen hair, large patches of alo­pecia may accidentally occur after pulling hairs. Hairs are easily pulled out without any pain and a trichogram shows nearly 100% anagen hairs.

14.2.1.4.8 Treatment In either case, the induced trauma, often the result of cultural, social, and cosmetic practices, is unintentional. Initially, hair loss is reversible if trauma is discontinued; however, permanent alopecia may result from chronic traction [40]. For large scarring defects, surgical intervention may be required [103].

14.2.1.5  

Triangular Alopecia

6

Synonyms congenital triangular alopecia, brauer nevus OMIM NA

14.2.1.5.1 Introduction Congenital triangular alopecia is manifested at 2–5 years of age by unilateral or, less frequently, bilateral patches of alopecia in the fronto-temporal region. Triangular alopecia is rarely present at birth or develops in adulthood.

14.2.1.5.2 History About 52 cases of congenital triangular alopecia have been reported so far.

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14.2.1.5.3 Epidemiology

14.2.1.5.7 Differential Diagnosis

Probably because the lesion is benign and non-progressive, an analysis in 6200 patients revealed 7 with triangular alopecia, a frequency of 0.11% [34]. Congenital triangular alopecia usually occurs sporadically but may exceptionally affect several members of a family [41].

The distinct clinical appearance characterizes the disease and helps to differentiate from androgenetic alopecia and alopecia areata.

14.2.1.5.4 Pathogenesis

In general, the real need of treatment should be discussed with parents and patients. However, surgical treatment reducing the alopecia area is possible.

The genetic basis of congenital triangular alopecia is not yet clear. It has been reported in association with phacomatosis pigmentovascularis, providing evidence that it may originate from loss of heterozygosity. Heterozygous individuals could be phenotypically normal. It may be a paradominant trait [41].

14.2.1.5.5 Clinical Features In the triangular region of frontal scalp, a localized alopecia is found. The lesion is usually unilateral but bilateral involvement may likewise occur (Fig. 14.16).

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14.2.1.5.6 Pathology The alopecic area contains a normal numbers of hairs, although virtually all are vellus or indeterminate follicles.

14.2.1.5.8 Treatment

14.2.2 Scarring Alopecia Localized scarring of the scalp in children is mainly found as aplasia cutis congenita. In addition, a severe physical, chemical trauma or a deep , fungal or viral infection of the scalp may result in a scarring alopecia after healing of the defect or infection.

14.2.2.1  

Congenital Aplasia Cutis

6

Synonyms aplasia cutis congenita, congenital defect of skull and scalp, congenital scalp defect, ACC, epitheliogenesis imperfecta OMIM 107600

14.2.2.1.1 Introduction Aplasia cutis congenita is a congenital condition in which skin, bone, and dura can be absent. In the majority of cases, the scalp is affected, limited to the dermis and epidermis.

14.2.2.1.2 History Aplasia cutis congenita was first described by Cordon in 1767 and more than 500 cases have been reported since [11].

14.2.2.1.3 Epidemiology

Fig. 14.16  Triangular alopecia (Brauer nevus) was found as a unilateral non-scarring alopecic patch in a 14-year-old boy

Aplasia cutis congenita is a rare condition with an estimated incidence of 2–3 cases per 10,000 newborns; 86% of all solitary lesions involve the scalp, although other parts of the body may be affected. Defects may involve the epidermis and dermis to varying degrees, and ap-

Hair Loss in Children

proximately 15% of the scalp defects also involve the underlying skull.

14.2.2.1.4 Pathogenesis Aplasia cutis congenita is typically sporadic. However, autosomal-dominant and rarely autosomal-recessive cases have been reported. The exact pathophysiology underlying aplasia cutis congenita is unknown; however, several factors have been implicated. These include intrauterine trauma, vascular compromise, teratogens such as infectious agents, and methimazole, an antithyroid medication. However, a hypothesis of disruptive mechanical forces of tension and stretching on embryonic skin and its underlying mesenchyme has been supposed. An animal model of aplasia cutis congenita may exist in transgenic mice over expressing the glucocorticoid receptor. These mice are born with generalized thin skin, decreased hair growth, and localized absence of skin at the cranium and umbilical regions [11].

14.2.2.1.5 Clinical Features Aplasia cutis congenita is a rare condition characterized by congenital absence of the epidermis, dermis, and subcutaneous tissue. It may occur as an isolated defect or associated with other anomalies. Vertex aplasia cutis typically ranges in size from 0.5 to 3 cm. The condition can present in isolation or with associated conditions such as limb anomalies or embryologic malformations (Fig. 14.17).

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14.2.2.1.6 Pathology Careful study due to the frequent association of aplasia cutis congenita with other congenital anomalies and a complete obstetric and family history of all affected individuals are required to identify possible specific teratogens, intrauterine infections, chromosomal abnormalities, or history of this condition among relatives. Ultrasound and magnetic resonance imaging are important diagnostic tools to determine the extension of the lesion.

14.2.2.1.7 Differential Diagnosis Diagnosis is made by characteristic clinical picture. However, small lesion with scarring alopecia at birth may not be noted. If discovered in older children, localized morphea should be excluded by skin biopsy in difficult cases.

14.2.2.1.8 Treatment In small defects, secondary wound healing will result in permanent scarring alopecia. A conservative approach consisting of daily antiseptic dressing may allow scalp epithelialization to improve conditions for secondary surgery. The rare larger scalp defects are prone to complications of hemorrhage and infection. For large defects, surgical intervention is required [11].

14.3

Diffuse Hair Loss

Diffuse hair loss is a symptom representing a broad spectrum of underlying diseases. Mainly, different types of non-scarring alopecia should be considered. However, some forms of scarring alopecia may appear as a diffuse type of hair loss.

14.3.1 Non-Scarring Alopecia

Fig. 14.17  Large defect with scarring alopecia in aplasia cutis congenita in a 2-day-old male term newborn. Magnetic resonance imaging revealed an underlying bone defect of the skull

In most cases of children presenting with diffuse hair loss, a telogen effluvium is diagnosed. The diffuse type of alopecia areata is rare, but this entity should be considered in differential diagnosis. Loose anagen hair is often found when parents complain of slowly growing hair. On the basis of numerous hair diseases and syndromes with congenital hypotrichosis or atrichia, this chapter may not include and discuss all known forms (see also Chap. 6 and review papers [2, 106]).

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14.3.1.1  

Telogen Effluvium

6

Synonyms telogen hair loss, telogen hair shedding OMIM NA

14.3.1.1.1 Introduction Generalized hair loss presenting as telogen effluvium is due to a parallel interruption of the anagen phase. Underlying causes are numerous and a careful diagnostic work up is mandatory to unravel the disorder.

14.3.1.1.2 History Due to the variety of underlying causes, it is difficult to define a distinct history of first description of telogen effluvium. Since underlying disorders such as iron deficiency or thyroid dysfunction exist over a long period, one may assume that diffuse hair loss is apparent, because the underlying diseases have been identified.

14.3.1.1.3 Epidemiology

14

Telogen effluvium is a common cause of diffuse hair loss in children. Rarely is dystrophic effluvium diagnosed. The underlying cause varies but as iron deficiency and thyroid dysfunction are not uncommon in children, these disorders should be considered in telogen effluvium. Also, diffuse hair loss in children may occur after severe bacterial or viral infections.

14.3.1.1.4 Pathogenesis Telogen effluvium is caused by the abrupt synchronous induction of growing hairs (anagen) into telogen phase. If an acute interruption of anagen by a highly toxic event occurs, anagen-dystrophic hairs may result instead of telogen hairs. This process can be triggered by a wide variety of systemic metabolic disorders and drugs. However, drugs are rather rarely the cause of telogen effluvium in children in contrast to adults. In chemotherapy hair loss is also noted, similar to adults.

14.3.1.1.5 Clinical Features Children usually present with a history of abrupt generalized diffuse hair shedding and thinning over the entire scalp. In telogen effluvium the underlying cause may precede the onset of hair loss by about 3  months or less.

 

Clinically, hair volume may be normal or diminished. A hair pull-test is positive throughout the scalp; usually 6–20 pulled hairs are painlessly extracted, provided the child’s hair has not been shampooed for 48 hours.

14.3.1.1.6 Pathology Pathological induction of telogen in children can often be due to iron deficiency, thyroid dysfunction, and after systemic infections with fever. Less often, underlying causes such as nutritional disorders, malabsorption, renal or hepatic failure and surgery are responsible. Common causative drugs in children include anticonvulsants, anticoagulants and antidepressants; rarely, hormones, retinoids, beta-blockers, angiotensin-converting enzyme inhibitors, and cholesterol-lowering agents are the cause. In case of predominantly dystrophic hairs, a severe underlying cause such as an acute metabolic disorder or failure should be considered; causative drugs are mainly chemotherapeutics. A helpful, but for children painful, diagnostic tool is the trichogram technique. After pulling 50 hairs from the frontal and occipital regions, hairs are embedded in hair mount and analyzed under the microscope. More than 15% telogen hairs in both areas is indicative of diffuse telogen hair loss. An increased number of dystrophic hairs (> 3%) could be due to a severe underlying cause.

14.3.1.1.7 Differential Diagnosis The differential diagnosis of telogen effluvium in children usually includes the diffuse type of alopecia areata and loose anagen hair. In alopecia areata, the trichogram is not always helpful since telogen and dystrophic hairs are found in the hair mount. Close inspection of the scalp, face or body often reveals small patchy areas of alopecia and nail pitting. Sometimes a history of former patchy hair loss in one area of the scalp or a positive family history is found. In doubtful causes a skin biopsy is necessary, showing typical signs of alopecia areata. Loose anagen hair is easily identified in the trichogram presenting with predominantly anagen hairs and lack of telogen or dystrophic hairs.

14.3.1.1.8 Treatment After having reversed and treated the underlying cause, hair usually regrows within the next 3 months without any additional treatment. Counseling of parents to remain patient is important to exclude any unnecessary additional treatment.

Hair Loss in Children

14.3.1.2

 

Alopecia Areata Diffusa, Totalis or Universalis

6

Synonyms Pseudopelade, alopecia universalis OMIM 104000

14.3.1.2.1 Introduction Alopecia areata diffusa is a chronic inflammatory disease characterized by acute onset of non-scarring hair loss without epidermal signs of inflammation.

14.3.1.2.2 History For further details of history please see Sect. 14.2.1.1.

14.3.1.2.3 Epidemiology For further details of epidemiology please see Sect. 14.2.1.1.

14.3.1.2.4 Pathogenesis In alopecia areata, Galbraith and Pandey [18] found that the distribution of Th1/Th2 phenotypes differed between patients with the patchy form of the disease and patients with totalis/universalis disease. There was no significant difference in the distribution of the phenotypes for the second system. The results suggested genetic heterogeneity between the two forms of alopecia areata. The tumor necrosis factor alpha (TNF-α) gene is a closely linked locus within the major histocompatibility complex on chromosome 6 where this gene maps and may play a role in the pathogenesis of the patchy form of the disease. Current reports of a manifestation and progress of alopecia areata totalis and universalis in patients receiving TNF-α- blocking agents may contradict the notion that TNF-α is as central to the pathogenesis of alopecia areata as previously believed, and the role as a key target should be reconsidered [33].

14.3.1.2.5 Clinical Features Clinical features of alopecia areata include its severe forms alopecia areata totalis and universalis. In some cases, a diffuse form may be present initially. Usually, remaining patchy lesions with non-scarring alopecia represent the diagnostic clue in these forms.

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14.3.1.2.6 Pathology In alopecia areata diffusa patchy lesions are mainly absent on the scalp, and trichogram analysis shows elevated telogen and dystrophic hairs. Thus, diagnosis is made by additional features such as sudden onset of hair loss, nail involvement, patchy hair loss in other regions of the body or a positive family history of alopecia areata. Other causes for telogen effluvium such as metabolic disorders, anemia, hormonal dysregulation (e.g., thyroid disease) should be excluded.

14.3.1.2.7 Treatment See treatment as described in localized alopecia areata in Sect. 14.2.1.1 and Chap. 15.

14.3.1.2.8 Differential Diagnosis Alopecia areata universalis should be distinguished from atrichia with papular lesions and congenital hypotrichosis. In alopecia areata skin is unaffected without any epidermal lesions. In difficult cases skin biopsy reveals characteristic peribulbar lymphocytic infiltrate in alopecia areata.

14.3.1.3  

Loose Anagen Hair

6

Synonyms loose anagen hair syndrome, loose anagen syndrome OMIM 600628

14.3.1.3.1 Introduction The loose anagen hair syndrome (LAS) is a sporadic or familial hair disorder that primarily affects children but may occasionally be seen in adults.

14.3.1.3.2 History More than 100 white patients with LAS have been described in the literature by Price and Gummer in 1989 [72]. The most important problem in diagnosing LAS is that the weak hair shaft–hair follicle adhesion characterizing the disorder also occurs in a small proportion of follicles of clinically unaffected individuals. This may lead to over diagnosing of LAS, particularly when the diagnosis is based mainly on microscopic than on clinical features.

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14.3.1.3.3 Epidemiology Loose anagen hair is typically diagnosed in childhood, usually after an age of 2 years, with the mean age of reported patients being 6 years. Adult cases have occasionally been described, mostly in parents of affected children. The condition has been reported more frequently in female than in male patients (ratio, 6:1), but this may be owing to under-reporting in male patients: the most important clinical sign, the failure of hair to grow long, might not be evident in boys, who usually keep their hair short.

14.3.1.3.4 Pathogenesis

14

It is believed that LAS results from a premature keratinization of the inner root sheath that produces an impaired adhesion between the cuticle of the inner root sheath and the cuticle of the hair shaft. The outer root sheath–inner root sheath adhesion is involved in a number of cases [96]. Mutations in the gene encoding for the companion-layer keratin (K6HF) in some members of families with LAS have been found. The genetic basis of LAS may involve more than one gene encoding for keratins expressed in the inner root sheath or in the companion layer. Another possible candidate may be the gene encoding for the new keratin (K6IRS) specific for the inner root sheath [96].

 

shows 70%–100% anagen-dysplastic (syn. loose anagen) hairs in comparison with the 10% anagen-dysplastic hairs found on the trichogram of normal adults. Slight flattening and longitudinal grooving has been noted on electron microscopy [39]. Loose anagen hair syndrome is in most cases isolated, but it also occurs in association with hereditary or developmental disorders. These include coloboma, Noonan syndrome, hypohidrotic ectodermal dysplasia, EEC syndrome, trichorhinophalangeal syndrome, nail-patella syndrome, and FG syndrome (personal observations of the authors). Patients with LAS and alopecia areata have also been reported [96].

14.3.1.3.7 Differential Diagnosis Presence of loose anagen hairs at the pull-test or on trichogram is, however, not specific for LAS since it may also occur in healthy individuals. Trichotillomania should be excluded by clinical pattern.

14.3.1.3.8 Treatment Parents of children should be advised to use a mild hair care routine to reduce fraction or trauma to hair, since it is easy to pull out. The length and density of hair gradually increase with age, but anagen hairs may remain loosely anchored even in adulthood [65, 72].

14.3.1.3.5 Clinical Features In LAS, anagen hairs are easily pulled from the scalp. An early age of onset is common. The majority of patients are blond girls, aged 2–5 years, but both sexes and also those with dark hair can be affected (Fig. 14.18). The hair is relatively sparse and does not grow long. Usually the hairs are not fragile and there are no areas of breakage. Three different phenotypes of LAS exist: (1) patients with type A LAS have sparse hair that does not grow long, and they often present with patches of dull, unruly hair; (2) patients with type B LAS have diffuse or patchy, unruly hair; and (3) patients with type C LAS have increased hair shedding [96].

14.3.1.3.6 Pathology Diagnosis of LAS relies on number and percentage of hairs at the pull-test and on anagen-dysplastic hairs (anagen hairs devoid of sheath) in the trichogram. In case of LAS, pull-test reveals more than 3–10 hairs, easily and painlessly to pluck. The trichogram

Fig. 14.18  Gradual hair loss was noted in a 5-year-old boy. No other anomalies of hair were found. Physical and mental development were normal and hypotrichosis simplex, localized type, was diagnosed

Hair Loss in Children

14.3.1.4  

Hypotrichosis Simplex

6

Synonyms hereditary hypotrichosis simplex, pure hypotrichosis, HTS OMIM 605389

14.3.1.4.1 Introduction Hypotrichosis simplex is a genotrichosis characterized by two types: a hair defect limited to the scalp or affection of the scalp and body hair; both in the absence of other ectodermal or systemic abnormalities.

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14.3.1.4.6 Pathology Examination with both light microscopy and polarizing light microscopy shows dystrophic, thin hair bulbs but no structural abnormalities. Microscopic examination of a scalp biopsy specimen reveals a reduced number of hair follicles. No inflammatory infiltrates should be present.

14.3.1.4.7 Differential Diagnosis

A localized form was first described by Toribio and Quinones in 1974 with several subsequent reports [95]. Baumer and colleagues described a non-consanguineous Italian family with hypotrichosis simplex in an auto­ somal-dominant pedigree pattern [8].

In contrast to the total and permanent absence of hair in congenital atrichia, hair is present in hereditary hypotrichosis simplex but is diffusely thinned. Another form of isolated hypotrichosis, the Marie Unna type, is distinguished from hypotrichosis simplex by the presence of a twisting hair dystrophy. Associated ectodermal or other defects should be excluded in hypotrichosis simplex. Premature presentation of androgenetic alopecia is ruled out by trichogram or video-assisted phototrichogram showing a decreased anagen/telogen ratio in the frontal versus the occipital region.

14.3.1.4.3 Epidemiology

14.3.1.4.8 Treatment

Hypotrichosis is a relatively common feature of a number of complex hereditary syndromes. However, the isolated variant hypotrichosis simplex is particularly uncommon.

No effective treatment is available in this inherited condition.

14.3.1.4.2 History

14.3.1.5

14.3.1.4.4 Pathogenesis A genome wide linkage analysis resulted in a positive 2-point lod score of 3.31 at θ=0 at 18p11.32-p11.23 [8].

14.3.1.4.5 Clinical Features Hypotrichosis simplex can be divided into two main forms: generalized (or universal or total) in which the defects involve all the body hair, and localized (hereditary hypotrichosis of the scalp) in which hair loss is limited to the scalp with the rest of the pilary system being normal. Usually, children present with normal hair at birth and during the first years of life. They experience a progressive, gradual loss of scalp hair, beginning in the middle of the first decade and leading to almost complete loss of scalp hair by the third decade. A small amount of sparse, fine, short hair can remain in some children. No associated abnormalities have been reported. Phenotypic variation has to be considered (Fig. 14.18).

 

Congenital Hypotrichia Marie Unna

6

Synonyms Marie Unna hypotrichosis, Marie-Unna hypotrichosis, Marie Unna hereditary hypotrichosis, hypotrichosis of Marie Unna, hereditary trichodysplasia OMIM 146550

14.3.1.5.1 Introduction Marie Unna hypotrichosis is a rare autosomal-dominant congenital alopecia characterized by progressive hair loss starting in early childhood.

14.3.1.5.2 History Marie Unna is accredited with the first description in 1924 of a family with sparse or absent hair at birth, very coarse regrowth of hair in early childhood, and hair loss mainly at the vertex after puberty [5, 53].

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14.3.1.5.3 Epidemiology Marie Unna hypotrichosis is a rare autosomal-dominant condition in which abnormalities are confined to hair shaft structure and hair density. Several pedigrees have been described [108].

14.3.1.6  

Atrichia with Papular Lesions

6

Synonyms papular atrichia, generalized atrichia with rickets resistant to 1,25-dihydroxyvitamin D, OMIM 209500

14.3.1.5.4 Pathogenesis

14.3.1.6.1 Introduction

There is evidence for linkage to the disease on chromosome 8p21 close to the hairless locus. Recently, an affected family was mapped to a 17.5 cM region between markers D1S248 and D1S2345 [108].

Congenital atrichia with papular lesions is a rare, autosomal-recessive form of total alopecia and mutations in the hairless gene have been implicated in this disorder.

14.3.1.5.5 Clinical Features Affected children are born with little or no eyebrows, eyelashes, or body hair. Characteristically coarse, wiry, twisted hair develops in early childhood and is followed by the development of alopecia after puberty. The hair loss presents as an isolated feature in these patients. However, follicular keratosis and milia-like facial lesions are often found.

14

 

14.3.1.5.6 Pathology In light microscopic or electron microscopic analysis, both torsion and longitudinal grooving of the hair shaft or pili torti are found [5].

14.3.1.5.7 Differential Diagnosis Apart from hypotrichosis simplex, other hypotrichoses with associated defects should be differentiated. Progressive patterned scalp hypotrichosis and wiry hair similar to that seen in Marie Unna hereditary hypotrichosis differ from those of Marie Unna, including absence of signs of abnormality at birth, relative sparing of body hair, distal onycholysis, and intermittent cosegregation with autosomal-dominant cleft lip and palate.

14.3.1.5.8 Treatment Hypotrichia Marie Unna is often aggravated at puberty, leading to scarring alopecia of variable severity [53]. No effective treatment is yet available.

14.3.1.6.2 History Atrichia with papular lesions was first described in 1954 by Damste and Prakken [28]. Attention has recently focused on this disease because of the description of several kindred with generalized atrichia associated with a mutation of the human homolog of the well-known murine hairless gene [1] (see also Chap. 6).

14.3.1.6.3 Epidemiology A phenotypic heterogeneity in inherited atrichias caused by mutations in the hairless gene may explain the low prevalence of this disorder, considering that pathogenetic mutations in hairless gene have been found in distinct ethnicities around the world. Therefore, it is likely that congenital atrichia with papular lesions is far more common than previously thought and is often mistaken for its phenocopy, the putative autoimmune form of alopecia universalis [101].

14.3.1.6.4 Pathogenesis The hairless gene was recently cloned and sequenced on human chromosome 8p12 and segregates with the disease in an autosomal-recessive manner [64]. A novel 11-bp insertion mutation, G202 (InsCTTCCCCCAGG), in exon 2 of the hairless gene was identified in a Pakistani consanguineous family affected by congenital atrichia. The insertion results in the expansion of an 11-bp tandem repeat, which introduces a translational frameshift leading to a downstream premature termination codon. As has been clarified, this is a non-inflammatory genetic condition with no relationship to alopecia areata, which is an autoimmune condition [101]. Mutations in the hairless gene (HR) have been found in this phenotype in both mice and humans [60].

Hair Loss in Children

14.3.1.6.5 Clinical Features Apparently normal hairs are present at birth in most patients, but these neonatal hairs are usually shed within the first months of life and are never replaced. In individual cases, the shedding of the hair occurs during the first 2–3 years of life. At approximately 2 years of age, affected patients begin to develop multiple follicular papules and variations in the structure and morphology of the hair follicle remnants have been reported [91]. Another rare condition to consider in atrichia is rickets resistant to 1,25-dihydroxyvitamin D. These patients present with loss of some or all scalp, body, and facial hair (with or without loss of eyelashes), typical within the first 15 months of life [42].

14.3.1.6.6 Pathology Histologic examination of affected scalp skin shows the absence of mature hair follicle structures and keratinous cysts in the dermis. Children resistant to 1,25-dihydroxyvitamin D have clinical and radiological signs of rickets, such as bowed limbs, extremity fractures, and diffuse osteopenia, accompanied by laboratory abnormalities including marked hypocalcemia with secondary hyperparathyroidism and elevated levels of 1,25-dihydroxyvitamin D and alkaline phosphatase.

14.3.1.6.7 Differential Diagnosis Between the ages of 2 and 26 years, patients develop numerous keratinous, papular cysts resembling milia on the head, upper torso, and extremities, distinguishing them from patients with alopecia totalis/alopecia universalis. In the first months of life, it may be difficult to identify vitamin-D-resistant rickets, because clinical signs of rickets may not yet be apparent [57].

14.3.1.6.8 Treatment Due to the genetic pathogenesis of the disease no effective treatment is known to induce regrowth of hairs.

14.3.2 Scarring Alopecia Scarring alopecia in children is very rare, but should be excluded clinically in cases of localized alopecia by dermascopic evaluation of the scalp. In case a scarring alopecia is suspected a skin biopsy is useful to specify the cause.

Chapter 14

14.3.2.1

 

303

Keratosis Follicularis Spinulosa Decalvans

6

Synonyms keratosis pilaris atrophicans, keratosis follicularis spinulosa decalvans cum ophiasis OMIM 308800

14.3.2.1.1 Introduction Keratosis follicularis spinulosa decalvans is a rare, Xlinked disorder affecting both the skin and eyes [3]. In the case of follicular hyperkeratosis, variable degrees of inflammation and secondary atrophic scarring are characteristic features of keratosis follicularis spinulosa decalvans.

14.3.2.1.2 History Keratosis follicularis spinulosa decalvans is a rare disorder characterized by widespread keratosis pilaris and scarring alopecia of the scalp and eyebrows. Onset of the skin disease is in early childhood but with scalp involvement occurring in the teen years [6]. During infancy, keratosis pilaris begins on the face and, by childhood, progresses to involve the trunk and extremities. Sometime during childhood or up to the early teenage years, a cicatricial alopecia of the scalp and eyebrows develops and is the hallmark of this disorder [76]. Ocular abnormalities and palmoplantar keratoderma are less frequent associations. Siemens (1925) described [84] two families with Xlinked inheritance of keratosis follicularis spinulosa decalvans. According to information available, one family was from Bavaria and the other from the Netherlands. Siemens personally investigated two members of the Dutch family on the invitation of Lameris, who had reported the cases as ichthyosis follicularis. Two weeks after his visit to Lameris, Siemens encountered the index cases of the Bavarian family. The ophthalmologic features of the Lameris family were reported by Rochat in 1906 [66].

14.3.2.1.3 Epidemiology X-linked dominant inheritance has been reported in several families with keratosis follicularis spinulosa decalvans, with men more severely affected. Genetic studies on a large Dutch and British pedigree have demonstrated linkage to Xp22.13-p22.2 [69].

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14.3.2.1.4 Pathogenesis

14.3.2.1.7 Differential Diagnosis

In keratosis follicularis spinulosa decalvans, the linkage to Xp22.13-p22.2 has previously been reported [69]. Analyses of other families do not support X-linked inheritance, thus suggesting genetic heterogeneity. An inflammatory follicular process results in destruction and scarring.

Acne keloidalis nuchae may be considered in the occipital scalp and posterior neck region, characterized by folliculocentric pustulopapules that scar, resulting in keloidal plaques. This typically affects adolescent men with dark skin. Acne keloidalis nuchae is classified under the mixed group of primary cicatricial alopecia, with an initially neutrophilic inflammatory infiltrate and a latter infiltrate consisting of a mixture of lymphocytes and plasma cells, with the formation of foreign body granulomata [37].

14.3.2.1.5 Clinical Features

14

 

Keratosis follicularis spinulosa decalvans is characterized by follicular hyperkeratosis of the skin and corneal dystrophy. Typically, keratosis pilaris begins on the face in infancy and may progress to become more widespread on the trunk and limbs. Affected males show thickening of the skin of the neck, ears, and extremities, especially the palms and soles. Scarring alopecia of the scalp subsequently occurs in childhood or early adolescence. Alopecia may be patchy or diffuse (Fig. 14.19). Loss of eyebrows, eyelashes may be present. Rarer features include palmoplantar keratoderma, atopy, photophobia, and ocular abnormalities, in particular corneal dystrophy. An ophthalmological evaluation is required to examine thickening of the eyelids with blepharitis and ectropion, and corneal degeneration.

14.3.2.1.6 Pathology The characteristic histological findings are dilatation of the hair follicle with keratin plugs, a perifollicular and perivascular lymphocytic infiltrate, and scarring. Stains should be negative for bacteria and fungi.

14.3.2.1.8 Treatment Effective therapeutic options for this disease are not known, but there have been anecdotal reports of the efficacy of oral etretinate and isotretinoin. Oral isotretinoin at 0.25 mg/kg daily can improve inflammation.

14.3.2.2  

Pseudopelade of Brocq

6

Synonyms pseudopelade Brocq, Brocq’s pseudopelade OMIM NA

14.3.2.2.1 Introduction The term pseudopelade describes a pattern of alopecia that is different to the classic “pelade” found in nonscarring alopecia areata. Pseudopelade is characterized by diffuse patches of scarring alopecia of unknown origin [17].

14.3.2.2.2 History The term pseudopelade was introduced by Brocq in 1905 [17]. Later reports defined it as an end-stage or clinical variant of various forms of scarring alopecia. A distinct entity or a “primary” form of pseudopelade may exist, but this has yet to be established with certainty.

14.3.2.2.3 Epidemiology Fig.  14.19  Keratosis follicularis decalvans was found in a 15-year-old girl presenting with scarring alopecic patches on the scalp. Follicular hyperkeratosis is seen in the border of the alopecic area

Pseudopelade is a pattern of alopecia that is rarely encountered and is very rare in children; familial occurrence has been reported [21].

Hair Loss in Children

14.3.2.2.4 Pathogenesis The pathogenesis of pseudopelade Brocq is unknown. Assuming that pseudopelade Brocq is an end-stage of other forms of scarring alopecia, the inflammatory infiltrate as seen in discoid lupus erythematosus or lichen planopilaris could cause disturbance of the stem cell area and lead to permanent destruction of the hair follicle [92].

14.3.2.2.5 Clinical Features Typically, discrete asymptomatic areas of alopecia are found on the scalp. In general, the disease is slowly progressive. Frequently, patches of scarring alopecia like “footprints in the snow” are found. Alopecic patches are irregularly shaped, widely distributed, and clustered on the scalp. The individual lesion is porcelain white and slightly atrophic.

14.3.2.2.6 Pathology The histopathological findings of pseudopelade have yet to be clearly defined. Biopsy shows reduced numbers of hair follicles and sebaceous glands, in some cases a sparse lymphocytic infiltrate is present.

14.3.2.2.7 Differential Diagnosis With regard to the scarring character of pseudopelade, it is important to bear this diagnosis in mind whenever one encounters a child with patchy or diffuse alopecia. Other forms of scarring alopecia such as lichen follicularis or cutaneous lupus erythematosus show clinically perifollicular erythema and scaling. Traumatic induction or aplasia cutis congenita are sharply demarcated and do not resemble the classical description “like foot prints in the snow” as found in pseudopelade.

14.3.2.2.8 Treatment There is no effective therapy to treat pseudopelade. If pseudopelade shows progression correlated with histopathologic mild lymphocytic infiltrate, a topical treatment with corticosteroid solution may be tried.

Chapter 14

Summary for the Clinician Age of onset, history, and associated symptoms are important factors to be considered. First, the age at onset may help to further narrow the disease. The most frequent causes of hair loss in 1- to 3-yearold children are hair shaft defects with increased fragility, alopecia areata, and mycotic scalp manifestations (tinea capitis). Amongst older children (aged 4–11 years), the most significant causes are alopecia areata, loose anagen hair, artificial hair loss (trichotillomania, traction alopecia), and hair loss of infectious origin (microsporia, tinea capitis, folliculitis). Amongst adolescents (aged 12–18 years), alopecia areata and early onset of androgenetic alopecia represent the most frequent reasons for a consultation (Table 14.1; [71]). The following compilation comprises the most important differential diagnoses, according to the age at onset and their clinical characteristics in children. This chapter does not emphasize hair loss in adolescents, e.g., androgenetic alopecia (see Chaps. 9, 10), although it is mentioned in Table 14.1 for the sake of completeness. As a second step, further diagnostic clarification of hair diseases in children is based on the patient’s personal and family history, a thorough clinical examination, as well as general and specific diagnostic procedures. The patient’s history provides information about the age of the patient when the initial manifestation occurred, the subsequent development of the disease and associated symptoms. In addition, the family history may illustrate the occurrence of the disease within members of that family. Important features of genotrichoses are the associated symptoms and anomalies; thus, the dermatologist or pediatrician should focus his or her attention on the evaluation of physical and mental development, and also take into consideration noticeable psychological problems of the child. On the one hand, the clinical assessment should consider whether the hair loss (effluvium) is localized or diffuse and whether it is scarring or nonscarring (Table 14.2). On the other hand, it is crucial to determine whether any hair shaft defects simulating hair loss (Table 14.3) are present, or if decreased hair density (hypotrichosis, atrichia, and alopecia) is a result of prior shedding. Accordingly, a thorough clinical examination of the entire head and body is necessary, in order to evaluate the pattern of hair growth, variances in nail growth, impaired vision, defective hearing or dysfunction of

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perspiration. Furthermore, the scalp should be examined regarding signs of inflammation, dandruff and scaling, scarring, edema or other skin symptoms. In addition, the hair quality, color, roughness, and tendency to breakage should be critically evaluated.

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Chapter 14 103. Welch TB, Boyne PJ (1991) The management of traumatic scalp injuries: report of cases. J Oral Maxillofac Surg 49: 1007–1014 104. Whiting DA (1989) Localized trichorrhexis nodosa.J Am Acad Dermatol 20: 854 105. Whiting DA (1999) Traumatic alopecia. Int J Dermatol 38 Suppl 1: 34–44 106. Wiederholt T, Poblete-Gutierrez P, Frank J (2003) Genetically induced hair diseases. Hautarzt 54: 723–731 107. Wolf B (2002) Children with profound biotinidase deficiency should be treated with biotin regardless of their residual enzyme activity or genotype. Eur J Pediatr 161: 167–168 108. Yang S, Gao M, Cui Y, Yan KL, Ren YQ, Zhang GL, Wang PG, Xiao FL, Du WH, Liang YH, Sun LD, Xu SJ, Huang W, Zhang XJ (2005) Identification of a novel locus for Marie Unna hereditary hypotrichosis to a 17.5 cM interval at 1p21.1–1q21.3. J Invest Dermatol 125:711–714.

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Chapter 15

Alopecia Areata Pia Freyschmidt-Paul, Rolf Hoffmann, Kevin J. McElwee

 

 

Synonyms pelade



15

6

Key Features

• Alopecia areata (AA) is a reversible, initially patchy

• Alopecia areata is regarded as a T-cell-mediated

•

•

hair loss most commonly involving the scalp although other regions of the head, including eye­ lashes and beard, may also be affected. The disease may sometimes lead to complete baldness of the scalp (alopecia areata totalis) or of the entire body (alopecia areata universalis). The course of AA is usually characterized by phases of acute hair loss followed by spontaneous hair regrowth and waxing and waning of the lesions. However, in severe forms hair loss can persist for many years or even life. Typical nail changes of AA are pitting, transversal grooves, red spotted lunulae or trachyonychia. Histopathological features of AA include perifollicular and intrafollicular lymphocytic infiltrates involving only anagen hair follicles with subsequent miniaturization of these structures.

• •

autoimmune disease of the hair follicle that is mediated by CD4+ and CD8+ T-lymphocytes. As with other autoimmune diseases, AA most likely has a polygenic character, where susceptibility is dictated by several major genes and the phenotype may be modified by numerous minor genes. The most effective treatment for severe AA is the application of a contact sensitizer, while limited AA can be treated by intralesional corticosteroids or clobetasol propionate 0.05% ointment under occlusion. Pulse therapy with systemic corticosteroids or psoralen UV A (PUVA) is often used but neither has yet been proven in controlled studies to be effective in AA.

 

Contents 15.1 15.2 15.3 15.4 15.4.1 15.4.1.1 15.4.1.2 15.4.2 15.4.2.1 15.4.2.2 15.4.2.3

Introduction  . . . . . . . . . . . . . . . . . . . . . . . . . History  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology  . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis  . . . . . . . . . . . . . . . . . . . . . . . . . Genetics  . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rodent Models  . . . . . . . . . . . . . . . . . . . . . . . Humans  . . . . . . . . . . . . . . . . . . . . . . . . . . . . Immunology  . . . . . . . . . . . . . . . . . . . . . . . . Susceptibility Modifying and Causal Factors in AA  . . . . . . . . . . . . . . Disease Activation Mechanisms in AA  . . . Modes of Immune System Action on Hair Follicles Leading to Hair Loss  . . .

  312   312   312   312   312   313   313   315   315   316   317

15.4.2.4 15.5 15.6 15.7 15.8 15.8.1 15.8.1.1 15.8.1.2 15.8.1.3 15.8.1.4 15.8.2 15.8.2.1

Modes of Hair Follicle Response to Immune Activity Leading to Hair Loss  Clinical Features  . . . . . . . . . . . . . . . . . . . . . Pathology  . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis  . . . . . . . . . . . . . . . . . Treatment   . . . . . . . . . . . . . . . . . . . . . . . . . . Immunosuppressive Treatments  . . . . . . . . Corticosteroids  . . . . . . . . . . . . . . . . . . . . . . Topical Corticosteroids   . . . . . . . . . . . . . . . Intralesional Corticosteroids   . . . . . . . . . . Systemic Corticosteroids   . . . . . . . . . . . . . . Psoralen UV A Therapy   . . . . . . . . . . . . . . . The 308-nm Excimer Laser   . . . . . . . . . . . .

  318   320   322   322   322   323   323   323   324   324   325   325

312

Pia Freyschmidt-Paul et al. 15.8.3 15.8.3.1 15.8.3.2 15.8.3.3 15.8.3.4 15.8.3.5

15.1

Immunomodulatory Treatments  . . . . . . . . Diphenylcyclopropenone and Squaric Acid Dibutylester   . . . . . . . . . Treatment  . . . . . . . . . . . . . . . . . . . . . . . . . . . Side-Effects  . . . . . . . . . . . . . . . . . . . . . . . . . . Studies  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mode of Action  . . . . . . . . . . . . . . . . . . . . . .

  325   325   325   325   326   326

Introduction

Alopecia areata (AA) is a common disease of men, women and children. Even though it is potentially always reversible, it may sometimes lead to complete baldness of the scalp or of the entire body and, in severe forms, hair loss can persist for many years or even life. Hence, AA is psychologically and socially disturbing for patients and a therapeutic challenge for the dermatologist.

15.2

History

Alopecia areata has been known about for at least 2000 years; it was first described in the year 57 AD.

15

15.3

Epidemiology

There is a lifetime risk for AA of 1.7% in the general popu­lation [72]. The disease affects both sexes with a slight predominance of females and may occur at all ages [75, 81, 93]. Even though there is a relatively high percentage of patients who have their first episode of AA before they are 20 years old (between 27% and 69.9% in different studies), children as young as 4 months and adults in their late seventies have been described to develop AA [75, 81, 93].

15.4

Pathogenesis

15.4.1 Genetics The genetics of an individual may play roles at multiple levels in the development of AA. While the presence of defective genes is possible in AA, it seems unlikely given that most other autoimmune diseases have not been shown to involve specific gene mutations. Rather, the primary mode of genetics’ contribution to AA seems to

  15.8.4 15.8.4.1 15.8.4.2 15.8.4.3

Other Treatments  . . . . . . . . . . . . . . . . . . . .   328 Irritant Contact Dermatitis – Anthralin   .   328 Minoxidil   . . . . . . . . . . . . . . . . . . . . . . . . . . .   328 Biologics  . . . . . . . . . . . . . . . . . . . . . . . . . . . .   328 Summary for the Clinician   . . . . . . . . . . . .   328

References   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   329

be the existence of functional gene alleles that code for increased disposal of the immune system towards auto­ immunity, and specifically towards AA development [4]. Major histocompatibility complex (MHC) gene alleles have been characterized that have a more favorable conformational structure for the presentation of antigens involved in autoimmunity. Other gene alleles may encode in favor of a pro-inflammatory state or they may be less capable of regulating inflammation. The genetic makeup of an individual is constant, but AA expression is variable over time. It seems likely that variation in the patient’s environment, and a complex interplay between environment and genes determine disease onset and expression for each individual [5]. Several studies suggest that AA has a genetic basis [88]. Alopecia areata in monozygotic twins with similar times of onset or similar hair loss patterns has been reported [2, 78]. Families with several generations of AA-affected individuals also suggest that AA may be a genetically determined disease [38, 76, 87]. There is a higher incidence of AA in genetically related individuals. Typically, 10%–20% of patients with AA indicate at least one other affected family member, whereas the lifetime risk of AA expression in the general population has been suggested to be 1.7% [72]. A recent study by Blaumeiser et al. [6] showed that estimated lifetime risks were 7.1% in siblings, 7.8% in parents, and 5.7% in offspring. The risk in second-degree relatives is slightly higher than the reported population risk. Age at onset in index patients and that in first-degree relatives were significantly correlated. This suggests that at least some people are genetically predisposed to develop AA. The triggers for the onset of AA may be environmental, but the resistance of the AA lesion to treatment, its persistence and regression, and its extent over the body may be influenced by the presence and interaction of multiple genes. A strong association has been observed between AA and trisomy 21 (Down’s syndrome). From 1000 patients and 1000 control subjects, Du Vivier and Munro observed 60 cases of trisomy 21 individuals with AA versus 1 control [16]. Carter and Jegasothy identified 19 cases of AA in 214 trisomy-21-affected patients and the statistical relationship is further supported in other

Alopecia Areata

studies [9, 92]. The genetic mutation for autoimmune polyendocrinopathy syndrome type 1 (AIRE, autoimmune regulator gene) is also associated with a 29%–37% prevalence of AA [5]. These studies suggest that candidate gene loci for AA susceptibility may be on human chromosome 21. Associations of AA with other autoimmune diseases have also been reported. Between 7% and 27% of AAaffected patients may also have a disease, including goiter presence, myxedema and Hashimoto’s thyroiditis [71, 77]. Co-expression of vitiligo and AA has also been reported at between 4% and 9% [63]. However, the statistical significance of these disease associations when compared to appropriate control populations has been disputed elsewhere. Numerous case reports detail the concordant presence of AA with other autoimmune diseases, such as diabetes and myasthenia gravis, although the statistical significance is unknown [49]. Alopecia areata has been proposed to be an autoimmune disease based on several indirect observations in humans and animal models of the disease [51]. Genetic influence has been clearly demonstrated in most other autoimmune diseases and one would expect that AA is no exception. Alopecia areata is clearly a complex disease; it does not segregate according to the rules of Mendelian inheritance [88]. As with other autoimmune diseases, AA most likely has a polygenic character, where susceptibility is dictated by several major genes and the phenotype may be modified by numerous minor genes.

15.4.1.1

Rodent Models

Two rodent models have been developed and characterized for use in AA research: the Dundee experimental bald rat (DEBR) and the C3H/HeJ mouse [59, 62]. Alopecia areata in both rodent models has been shown to be an autosomal polygenic trait with partial phenotype penetrance by analysis of breeding programs. To identify genes involved in the hair loss, mice were analyzed for linkage in a genome-wide scan with microsatellites. Using various tests, hints at linkage on chromosomes 5 and 8 with non-parametric Z scores of 2.4 (p